Chemo in Children

Cancer Treatment Reviews 38 (2012) 326
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Cancer Treatment Reviews

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Cytostatic drugs in infants: A review on pharmacokinetic data in infants

Hendrik van den Berg a,b,, John N. van den Anker c,d,e, Jos H. Beijnen f
a
Department of Pediatric Oncology, Emma Children Hospital Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Medicines Evaluation Board, The Hague, The Netherlands
c
Division of Pediatric Clinical Pharmacology, Childrens National Medical Center, Washington, DC, USA
d
Departments of Pediatrics, Pharmacology, and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
e
Department of Pediatrics, Erasmus MC-Sophia Childrens Hospital, Rotterdam, The Netherlands
f
The Netherlands Cancer Institute, Slotervaart Hospital, Amsterdam, The Netherlands
b
a r t i c l e
i n f o
Article history:
Received 11 January 2011
Received in revised form 21 March 2011
Accepted 24 March 2011
Keywords:
Cytostatic drugs
Infant
Pharmacotherapy
Pharmacokinetics
Oncology
Children
Infants
Ontogeny
Metabolism
Allometric scaling
a b s t r a c t
Below a certain age protocols in pediatric oncology on cytostatic drug therapy advise use, of other parameters such as weight for dosing; this instead of the most conventional parameter, i.e. body surface area. In
infants it is not uncommon that additional reductions are put on top of this for each cytostatic drugs to be
administered. The rationale behind this is often lacking. Differences related to the ontogeny of absorption,
distribution, metabolism and excretion are often not mentioned. Considering characteristics, such as lipophilia, ionization in relation to pH and size of the molecule and linking these characteristics with age
related shifts in the gastrointestinal tract, composition of the body and renal function; predictions on
pharmacokinetics (PK) in these infants can to a certain extent be made. More difcult are the shifts in
activity of phase I and II enzymes, which are often not known for a specic product. In this review data
on the ontogeny of relevant pharmacokinetic pathways in relation to the various cytostatic drugs and
data from pharmacokinetic (PK) studies in infants are presented.
This review shows that the administration of cytostatic drugs in infants is often based on limited or
even no data at all. Based on such a lack of evidence on treatment of infants with cancer; it should be
mandatory that in each infant treated with cytostatic drugs pharmacokinetic data are collected. Compiling these data in a global database would enable evidence-based drug therapy in infants with malignancies, resulting in a more effective treatment with less toxicity in this vulnerable population.
2011 Elsevier Ltd. All rights reserved.
Introduction
Adult cancer treatment is often based on the assumption that
each individual person metabolizes cytostatic drugs with the same
efciency. Individual differences might however either result in increased toxicity or less efcacy. Increased toxicity is dealt with in a
pragmatic way: dose reductions are often applied in the next
courses. Increased metabolism resulting in an increased relapse
rate is often not noted. Individual differences are, however, currently often linked to pharmacogenetic data.1,2 These pharmacogenetic factors are in pediatric pharmacotherapy superimposed on
developmental differences in relation to age, weight and body surface area. Especially in infancy substantial deviations in the pharmacokinetics (PK) of drugs are noted. Most pronounced are the
PK changes during the rst months of life. The response to the var Corresponding author. Address: Department of Paediatric Oncology, Emma
Children Hospital Academic Medical Centre, University of Amsterdam, Room
F8-242, P.O. Box 22700, 1100 DD Amsterdam, The Netherlands. Tel.: +31 20
5663050; fax: +31 20 6912231.
E-mail address: h.vandenberg@amc.uva.nl (H. van den Berg).
0305-7372/$ - see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctrv.2011.03.005
ious drugs (pharmacodynamics) may be different in children with

the same type of malignancy. However, in this review we will not
focus on the pharmacodynamics of the cytostatic drugs.
Reports on the PK of cytostatic drugs administered to infants
are very limited and often conned to a few studies and case reports in this age group; often only dealing with to adverse effects.
Examples of cytostatic drugs are reports on the excessive neurotoxicity of vincristine, resulting in hypotonia, feeding difculties
and paralysis of respiratory muscles.13 Unexpected side effects
during chemotherapeutic treatment of Wilms tumors have resulted in the recommendation to decrease the vincristine dosages
to 50.4 Still the situation on increased side-effects in infants has
not been resolved.5
In many protocols and some textbooks the evidence for dose
recommendations is less clear and sources often are not indicated.6
In most protocols dose reductions are proposed in infants, either
given as a percentage according to age or as calculations based
on body weight instead of the body surface area. Since liver volume
is correlated with body surface area and not to weight dosing
according to body surface area would be more relevant for drugs
with hepatic clearance only. However, the impact of ontogeny on
H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326
the metabolic capacity is completely neglected this way.7 Even in a

specic protocol for infants with acute lymphoblastic leukemia
(ALL) substantial dose reductions are mentioned irrespective of
the drug involved.8,9 The pharmacokinetic relevance of this is
doubtful.10,11 Although in pediatric oncology the age limit separating infancy from the toddler period is usually at 12 months, this review provides data on cytostatic drugs in children below the age of
2 years because these data are relevant and data in infants <1 year
were often too scarce. Before discussing the various cytostatic
drugs a summary is given on developmental changes relevant for
the PK of cytostatic drugs.
Absorption
The majority of cytostatic drugs are administered intravenously
to infants. In a few patients oral administration is used. These infants mainly suffer from leukemia and are treated with 6-mercaptopurine and methotrexate during the maintenance phase of their
treatment. Since there are currently no pharmaceutical formulations for oral use in infants marketed, extemporaneous formulations are standard of care. The quality of these extemporaneous
formulations is not secured and in case of tablets used as a starting
point, the matrix of excipients and the breaking strength are essential variables.12 Developmental factors important for the oral use
are gastric acid production, pepsin secretion, and gastric emptying.
Secretion of both gastric acid and pepsin are strongly decreased in
infancy. In addition this secretion is inuenced by enteral feeding.13,14 For phenobarbital it has been shown that higher dosages
are needed. For cytostatic drugs there are no data available.15 As
a result of this low acid and pepsin secretion increased absorption
related to state of ionization of weak acids (such as methotrexate),
is to be expected. Gastrointestinal motility is decreased in infancy
and gastric emptying is initially decreased.16,17 Since both methotrexate and 6-mercaptopurine (being the most often administered
orally administered drugs) are water soluble, changes in biliary
function and biliary composition are less important in infants with
a malignant disease.18,19 In general it is assumed that intestinal
surface is reduced in early childhood, despite the fact that if using
anthropometric data, the intestinal surface exceeds adult values.20,21 Differences in intestinal bacterial ora can be of major
inuence on pharmacokinetics (PK).22 As a result the formation
of the methotrexate metabolite, DAMPA, which is produced by
bacterial enzymes from methotrexate will be inuenced by the
kind of feeding. The drug-metabolizing enzyme function of the
intestinal wall in infants differs substantially from adults. Epoxide
hydrolase and glutathione peroxidase show little age dependency
in contrast to CYP1A1, which expression was shown to increase
with age.23 In contrast, young infants have a signicant expression
of CYP3A4 and P-gp m-RNA.24 But activity may be, despite expression, signicantly different. As such the intestinal CYP3A4 activity
was shown to increase during childhood.25 It should be mentioned
that both data on expression and drug-specicity of enzymes cannot be extrapolated from the liver to the intestine. In most infants
with a malignancy abnormal gastro-intestinal absorption will not
be recognized, since only a very limited number of drugs are
administered orally. In at least one of the most frequently used
drugs, 6-mercaptopurine, adverse reactions based on unexpectedly
low leukocyte counts will often be explained by TPMT polymorphism and not by deviations in absorption.
Distribution
For oral as well as parenteral medication several issues related
to drug distribution have to be considered; i.e. differences in body
composition such as total body water, extracellular water and body
fat, and altered binding to various plasma and tissue proteins. Lipid
soluble drugs have relatively larger distribution volumes in infants

as compared to older children due to the relatively higher amount
of fat. But also for water-soluble drugs larger distribution volumes
can be noted due to the larger extracellular water component. Inter-individual variation is common. Body composition changes
during development. Total water, especially extracellular water,
decreases during childhood. In the rst months after birth total
body fat increases, at later ages a relative decrease occurs. The
afnity of plasma protein is different depending on the type of
plasma proteins. The most important plasma protein is albumin.
Drug binding, both increased as well as decreased, differs for several drugs, due to differences in fetal versus non-fetal albumin
characteristics. Not only albumin inuences plasma binding. Other
plasma constituents do inuence drug binding as well. Examples
are plasma globulins and glycoproteins, which are generally decreased and free fatty acids which are commonly increased. Higher
binding as well as decreased binding was demonstrated for various
drugs. No data exist for cytostatic drugs.11,26,27
Metabolism
Although metabolism occurs in several tissues, the liver is probably the most important site for drug metabolism of cytostatic
drugs.
Liver volume and hepatic blood ow determine the amount of
drug that can be metabolized. Younger children have a relative
high liver volume, and liver volume has a close relation with body
surface area and hepatic blood ow.21 Microsomal protein content
is about two-third of the maximal concentration, which is reached
at an average age of 30 years.28 There is an increased intrinsic cytochrome P450 activity, however it is doubtful if that accounts for
the increased clearance of most P450 drug substrates in children.29
Phase I and II reactions are still in a process of maturation. In childhood and especially in neonates and infants the expression and
activity of both phase I and phase II enzymes differs in many aspects. In this respect, the above mentioned discrepancy in the
intestinal wall on expression of m-RNA and activity of CYP3A4
may be present in the liver as well. A point of caution is the interpretation of absolute activity in the body on basis of determination
of samples. Although it was shown that liver volume was a parameter correlated with pharmacokinetics.30 Allometric scaling
showed that the maximal activity of UGT1A4 was only reached
at the age of 18.9 years, instead of reaching it at the age of
1.4 years. This underscores the importance to take several factors
into account.31
Considering the developmental variations in activity of drug
metabolizing enzymes there is a major difference in drugs that
need a metabolic step prior to getting cytostatic activity versus
those drugs, where the parent drug is active as such. In pro-drugs
a slower rate of metabolic activation will lead to lower blood levels
of the active drug and extension of the period during which the active metabolite is present in the body. On the other hand developmental changes in elimination have consequences as well. If
elimination (hepatic or renal) is diminished this will lead to higher
blood concentrations and prolongation of the availability of the active metabolite/drug. In case elimination of the prodrug is normal,
blood levels of the active drug tend to be lower. However, this
might be reversed in case the metabolic step from pro-drug to active metabolite occurs at a slower rate. The nal result might be
that very low concentrations of active drug are present for a more
prolonged interval. Since toxicity and efcacy can be related to
either peak concentrations or duration of exposure or both, the effect on toxicity and efcacy cannot fully be deducted from the
scheme as depicted in Table 1.
Many drugs are substrates for phase I (oxidative) and/or phase
II (conjugative) metabolizing enzymes. Variant alleles cause in
Table 1
(A) Pharmacokinetic alterations related to changes in clearance of compounds formed after activation of prodrugs. (B) Pharmacokinetic alterations relating changes in elimination
of intrinsically active drugs.
Activation
A
Lower enzyme activity
Normal enzyme activity
Increased enzyme activity
Clearance
Decreased
Normal
Increased
Duration of exposure prolonged

Cmax undetermined
Cmax increased
Cmax increased

Cmax decreased
Duration of exposure normal
Cmax normal
Duration of exposure decreased
Cmax increased

Cmax decreased
Cmax decreased
Cmax increased

Cmax increased
Duration of exposure normal

Cmax normal

Cmax decreased
individuals considerable differences in metabolic capacity. These

differences add to the variance caused by developmental changes.
In line with this two main classes can be dened. Class I, including
amongst others CYP1A1, CYP1A2, CYP2E1 and CYP3A4, which are
well conserved and do not have important functional polymorphisms and Class II composed of CYP2B6, CYP2C9, CYP2C19,
CYP2D6 which are highly polymorphic.32 Additionally the activity
of metabolic enzymes can be different in the various tissues. Since
the liver is considered to be the site where most cytostatic drugs
are metabolized this report only deals with the ontogeny of hepatic
drug metabolic enzymes.28,33,34
Phase I enzymes
Cytochrome P450 system. The cytochrome P450 superfamily is a
large and diverse group of enzymes divided in 18 families. The
function of most CYP enzymes is to catalyze the metabolism
(mainly oxidation) of organic substances. About 23 enzymes are
relevant for the metabolism of drugs and toxins. It is currently believed that only families 1 through 3 are relevant for metabolism of
drugs.28 CYP enzymes catalyze oxidation of many compounds,
among them 90% of clinically prescribed drugs.
CYP1A: CYP1A1 is active in adults in the case of pulmonary
exposition to polycyclic aromatic hydrocarbons (tobacco smoking).
In unexposed individuals CYP1A1 is low or absent.35 The expression during fetal life has been extensively debated, but probably
the enzyme is only expressed in the rst trimester of fetal life.28
However, CYP1A comes to expression and plays a role in the
metabolism of procarbazine, dacarbazine, 5-uorouracil, etoposide
and the SN-38 metabolite of irinotecan.36
CYP1A2: CYP1A2 is a far more important enzyme as compared
to the CYP1A1. In fetal liver samples no activity was noted.37 A
steady increase in activity and protein levels is noted from birth
onwards: in neonates 45% of adult levels, in 13 months old infants 1015%, in 312 months old children 2025%, and in children
aged 19 years at 5055% of adult levels. Dietary differences inuence CYP1A2 expression. In formula-fed children a higher activity
was noted as compared to breast-fed infants.38,39 CYP1A2 is involved in the inactivation of dacarbazine, procarbazine, temozolamide and to a minor extent etoposide.32,4042
CYP1B1: CYP1B1 is mainly an extra-hepatic enzyme.43 Therefore
CYP1B1 is probably unimportant in drug metabolism. There is a debate on the expression in fetal liver; since it was only found in 3
out of 6 samples.44 However, these data were not conrmed in a
study including 63 fetal liver (2244 weeks gestation) and 12 adult
liver samples; m-RNA could not be detected.28,43 However, the enzyme is mentioned in relation to the metabolism of docetaxel and
mitoxantrone.32
CYP2A/B: The CYP2A family in humans is mainly represented by
3 members. Although CYP2A7 is found, this enzyme and its
variants are devoid of any activity.45 CYP2A6 is found in adult liver

tissue.46 In fetal samples in only one out of six samples CYP2A6
was detected.47 Crespi et al. found the enzyme in a single sample
originating from a child with a postnatal age of 17 weeks.48 Therefore, it can be concluded that development of activity of the enzyme starts somewhere in the rst year of life. In cytostatic
treatment CYP2A6 is a major enzyme in 5-uorouracil metabolism
and enhances the activation of the prodrug tegafur.49 As a consequence, if ever 5-uorouracil treatment in infants is indicated, this
orally taken prodrug is not a good choice. CYP2A6 is involved in
activation of cyclophosphamide into hydroxycyclophosphamide.
Since it is not the major enzyme active in this pathway the effect
of absent or decreased activity will be limited.50
For CYP2B6 only recently data on ontogeny became available. The
hepatic specimens originated from 217 patients (age range
10 weeks gestational age to 17 years, median age 1.9 months). Overall, CYP2B6 expression was detected in 75% of samples. However, the
percentage of samples with detectable CYP2B6 protein increased
with age from 64% in fetal samples to 95% in samples from donors
>10 years of age. There was a signicant, but only 2-fold, increase
in median CYP2B6 expression after the neonatal period (birth to
30 days postnatal) although protein levels varied 25-fold in both
age groups. The median CYP2B6 level in samples over 30 postnatal
days to 17 years of age (1.3 pmol/mg microsomal protein) was lower
than previously reported for adult levels (2.222 pmol/mg microsomal protein. The authors showed that there was no correlation
between CYP2B6 levels and CYP3A4, CYP3A5.1 or CYP3A7 activity.51
CYP2B6 is involved, as a major pathway, in the activation of
cyclophosphamide and ifosfamide. There is a close correlation
between CYP2B6 expression and activation of cyclophosphamide
into its hydroxy-metabolites. However, there are clear differences
between ifosfamide and cyclophoshamide. Probably it is the most
active pathway for cyclophosphamide.52 The activation trough 4hydroxylation for ifosfamide is to a large extent under control of
CYP3A4.53 Thiotepa undergoes desulfuration to an active derivate
with a long t by means of CYP2B6 and CYP3A4.54 Activation of
procarbazine is mediated by CYP2B6 as well.36 In adults there are
important racial differences. CYP2B6 1459C > T polymorphism is
noted in 13% of the Caucasian population and has shown to have
a lower activity as compared to other variants. Whether the differences related to CYP2B6 in gender, i.e. Caucasian females have a
lower expression, is relevant for children is yet unknown.55
CYP2C: In respect to the use of cytostatic treatment CYP2C9,
CYP2C18 and CYP2C19 are important. Data on CYP2C members
are often not differentiating between the various members of this
CYP family, whereas data on CYP2C18 are nearly absent.28 It was
shown that in early fetal samples CYP2C is as low as 1% of adult value. In the last trimester of pregnancy fetal liver concentrations
increase to 10%. These values increase from 25% of adult activity
level at the age of 5 months to 50% at the age of 10 years.56,57
The data on CYP2C9 and CYP2C19 are often not differentiated from
each other, but there are data that indicate that fetal expression of
CYP2C19 is found from 12 weeks onwards, i.e. 1020% of adult values. From birth onwards there is an increase during 5 months to
5075% of adult values. Up to 10 years of age CYP2C19
expression is highly variable. From puberty onwards normal adult
values are reached.58 However, PK data on phenytoin and warfarin
could not be explained by ndings related to the ontogeny of
CYP2C19.59,60
All CYP2 enzymes, but especially CYP2C19, are involved in the
activation of both cyclophosphamide and ifosfamide.53,61,62 Since
CYP2B6 is the most important enzyme for this step, the relevance
of other CYP2Cs will be quite limited provided that the activity of
CYP2B6 is not severely decreased in infancy. CYP 2C9 is to a limited
extent involved in the activation of tegafur and metabolism of idarubicin.32,49 As a consequence the low expression of the CYP2C
family will not have a major impact on the pharmacokinetics during infancy. Eighty-ve percent of inactivation of paclitaxel is induced by CYP2C8.63 However data on expression of this enzyme
in infancy are lacking
CYP2D6/8: CYP2D6 is involved in many oxidative processes. In
510% of the Caucasian population CYP2D6 activity is decient.40
In fetal samples activity, as measured by Treluyer et al., showed
an increase with advancing gestational age. Postnatal data on newborns from 7 to 28 days showed mean protein levels of 30% of adult
levels. Up to the age of 5 years there was an increment up to 70%.64
Only in adults, in contrast to children, a correlation of CYP2D6 protein and mRNA was detected. It was shown that there are many
transcripts resulting in inactive splice variants. Based on the discrepancies of protein content and m-RNA expression in children
it is suggested that at younger age more variants appear. This indicates that the ndings of Treluyer et al. do reect expression of
CYP2D6 m-RNA, but merely reect activity.65,66
In relation to cancer treatment in childhood, CYP2D6 might in
the future be important, since it is involved, as CYP3A4 is, in the
metabolism of the EGFR-inhibitor getinib (Iressa). CYP2D7 is a
variant carrying only a single insertion at position 137 in exon 1,
which causes premature termination. Functional activity of
CYP2D7 is not assumed.
CYP2E1: CYP2E1 is involved in metabolic pathways of several
therapeutics, including acetaminophen and halothane. The enzyme
also has an important role in the bioactivation of many small
molecular weight toxins, including ethanol, benzene, toluene,
N-nitrosodimethylamine, and halogenated alkanes.28 However the
relevance for cytostatic drug metabolism is limited. There is no correlation of fetal m-RNA expression and activity. RNA transcripts
show modest differences between fetal samples from the third
trimester and samples up to 28 days after birth. From 1 month until
1 year transcript levels increase to 50% of adult levels.67,68 Enzyme
protein levels augment from birth onwards to adult levels, which
are reached at 90 days postpartum.69 CYP2E1 is one of the inactivating enzymes in dacarbazine metabolism.
CYP3A family: The CYP3A4 family is involved in the metabolism
of about 50% of the drugs currently marketed.70 CYP3A4 is the most
important member of the CYP3A family, but the enzyme is prone to
wide inter-individual variation, mainly due to genetic factors.57,71
In fetal life the most predominant CYP3A is CYP3A7. CYP3A7 is
about 20-fold higher and decreases to adult levels at the age of
1 year. Generally speaking CYP3A7 remains the dominant enzyme
up to the age of 1 year.28,72 CYP3A4 and CYP3A5 are low expressed.7376 At the age of 1 month 3060% of adult values of
CYP3A4 are reached. Lower CYP3A4 levels are noted during childhood, especially in the younger age groups.28,72 During infancy,
CYP3A4 activity can during some periods even be slightly higher
as compared to adults. Later on lower activity is found and only
after the age of 10 years mean adult levels are reached.77 CYP3A5
in the liver exceeds CYP3A4 in African Americans, but due to genetic polymorphism it is only expressed in one third of Caucasians.78,79 The contribution of CYP3A4 and CYP3A5 can often not
be discerned due to the large overlap in substrate specicity.
CYP3A5 comes to expression during infancy.68,80
CYP3A4 is the major enzyme in the metabolism of many cytostatic drugs. There are no indications that CYP3A7 is an important
player in the metabolism of cytostatic drugs in adults, which might
be related to the low expression. Ifosfamide and cyclophosphamide
are to a large extent activated by CYP3A4/5, but are also involved in
the formation of inactive dechloromethyl- metabolites, which are
responsible for neurotoxicity. Inactivation by CYP3A4/5 is noted
for vinca-alkaloids, docetaxel, etoposide, irinotecan, taxol, teniposide, paclitaxel, busulfan, cisplatin, doxorubicine, topotecan,
mitoxantrone, thioTEPA, imatinib, genitib. ThioTEPA undergoes
desulfuration to an active derivate with a longer t by means of
CYP2B6 and CYP3A4.54 Within similar drug groups variations related to metabolic pathways exist. For instance docetaxel is metabolized for 6090% by CYP3A4/5, whereas CYP2C contributes for
85% in the metabolism of paclitaxel.81 It is unclear whether in infancy for a specic drug the contribution of each pathway is similar. Whether in infancy racial differences additionally inuence the
extent of use of the various pathways needs still to be investigated.
For instance clearance related to CYP4A5 of etoposide was lower in
people of African descent versus Caucasians.82 If this is also the
case in infants is unclear.
Flavin-containing monooxygenase system (FMO). In man only FMO1,

2 and 3 are active in drug metabolism.83 In liver there is a transition from fetal into adult expression. Initially FMO1 is the most
predominant enzyme; later on FMO3 is most abundant. FMO1 is
suppressed within 72 h after birth. Expression is detected only
after 1 month and before the age of 10 months. Intermediate
expression is noted up to the age of 11 years.84 In adults FMOs
dont play a relevant role in metabolism of cytostatic drugs. There
are no data that in infants this would be the case.
Alcohol dehydrogenase. Alcohol dehydrogenase is encoded by seven

genes. There is progressive expression of ADH of all three class 1
enzymes during human development.85 In early fetal life only
ADH1A has been detected in the liver using starch gel electrophoresis. Later on ADH1B and ADH1C appear. In preterm infants,
ADH1B is the most expressed enzyme. In adults ADH1A is low or
absent, ADH1B and ADH1C are equally expressed.85,86 However,
there is uncertainty on fetal expression of ADH1A, since m-RNA
(as determined by Northern blotting) showed no expression of
one of the two liver samples of unspecied fetal age.87 The relevance for cytostatic treatment in infants is limited. ADH only plays
a role in detoxication of aldophosphamide into alcophosphamide.
Other pathways in aldophosphamide metabolisms are ALDH and
GST, whereas the pathway leading to the most important active
compound, phosphoramide mustard is not inuenced by ADH.
Aldehyde dehydrogenase. Aldehyde dehydrogenase enzymes are a

group of enzymes catalyzing the oxidation of aldehydes to carboxylic acids. In mice there is decreased expression of all enzymes of
this family in fetal as well as in the early postnatal period.88 In
man there are no data on the ontogeny of these enzymes. The enzymes play a role in detoxication of cyclophosphamide; i.e. the
conversion of aldophosphamide into carboxy-phosphamide. For
tumors, resistant for cyclophosphamide increased levels of aldehyde dehydrogenase activity were found.89 If the ontogeny in humans is similar to mice, increments of the active compounds of
cyclophosphamide are likely.
Aldehyde oxidase (AOX). Aldehyde oxidase is to a minor extent involved in the metabolism of 6-mercaptopurine and methotrexate.
Although the activity in fetal liver was found to be 30% of the adult
value, in neonatal erythrocytes the activity was found to be 50%
higher than in adults.90,91 In Japanese neonates activity was
1015% of the activity in adults, as measured by urinary excretion
of the relevant oxidation product. At the age of 1 year there was a
linear increase to adult values.92 For cytostatic treatment in infants
the decreased activity of the enzyme is of limited importance for
methotrexate as well as 6-mercaptopurine. The major pathway
for methotrexate is renal excretion. For 6-mercaptopurine thiopurinemethyltransferase (TPMT) is the major enzyme in the metabolic decay of the drug.
Phase II enzymes
Glutathione S-transferase (GST). GST forms a family of enzymes
from 16 genes and six subfamilies.93 There is a great overlap for
substrate.94 Paci and Rane showed for styrene oxide that there
was a nearly threefold decreased activity in fetal tissue as compared with adult liver tissue.95 During ontogeny there are shifts
in respect to the various enzymes. For GSTA2 an increase is noted
after birth during the rst 2 years of life. Also GSTA1 shows an increase and, as compared to GSTA2, there is a somewhat higher liver
protein content during the rst 1.5 years of life. For GSTP a decrease from fetal values to nearly no expression is seen. GSTM
has a low expression in fetal liver, but in neonates it shows a nearly
similar expression as compared to adults.96 GST is involved in the
formation of 4-glutathionyl-cyclophosphamide from aldophosphamide. Considering the data of Paci en Rane, increased levels of the
active metabolites of cyclophosphamide are to be expected. GST
also plays a role in the metabolism of busulfan and chlorambucil,
which may explain increased toxicity due to delayed elimination.
Sulfotransferase (SULT). Sulfonyltransferases are categorized in four
families. Limited data exist on the various subtypes. For the SULT
1A family a decrease in expression, increasing 3-fold to levels in
the adult age, were described.97 There is a difference in the expression of subtypes in relation to ontogeny. SULT1A1 is in the fetal,
neonatal and adult period present at the same level.98 SULT1A3
protein is decreased postnatally (10-fold).99101 SULT1E1 decreases
during fetal life and infancy to adult low levels.98 For SULT2A1 a
steady increase from low fetal levels to adult levels was found.98
For the other SULT enzymes limited data are available. SULT enzymes are in adults not involved extensively in metabolism of
cytostatic drugs, and there are no data in infants.
UDP glucuronyl transferase (UGT). UGT enzymes catalyze the conjugation of hydrophobic compounds to form b-D-glucopyranosiduronic acids, which are excreted renally and in the bile.102 Two
families exist, i.e. UGT1 and UGT2, and in total 16 functional genes
are known. UGT1A1, responsible for bilirubin glucuronidation, is
nearly undetectable in fetal liver. Enzyme expression increases
independent of gestational age immediately after birth, and
reaches normal adult values after 36 months. UGT1A3 level is at
birth about 30% of adult value.103 UGT1A6 is in fetal liver 110%
of adult levels. Following birth there is a slow increase in expression and at the age of 6 months 50% of adult levels are expressed;
its activity is only complete after puberty. For UGT2B7 there is an
increase after birth from 10% to 20% to adult levels, reached at the
age of 23 months.104 Analysis of 13 UGT enzymes according to
three age cohorts, i.e. 612 months, 1318 months and
1924 months revealed no differences for UGT1A1 and UGT2B7
transcripts, as compared to adult samples. For UGT1A9 there was
a progressive increase with age, whereas UGT2B4 was constantly
low at a level of 35% of adult values. For both enzymes regulation
of expression extends beyond 2 years of age.105 A progressive
increase in UGT2B7 activity across ve age groups,<1 year of age,

15 years of age, 611 years of age, 1217 years of age, and adults
has been noted in another study. However, after allometric scaling
using the 3/4 power rule normal values were predicted at the age
of 23 months.106
UGT enzymes are involved in metabolism of anthracyclines,
topotecan and irinotecan. In addition to the age related variability
in activity of UTP1A1 there are differences in activity related to the
polymorphic expression of this enzyme. It was shown that the
UGT2A128 allele was related to a lower rate of conjugation of
SN-38, an active metabolite of irinotecan, resulting in excess toxicity.107 The camptothecans are metabolized through UGT1A9. As a
result progressive improvement of clearance is to be expected during several years following birth.
N-acetyltransferase (NAT) and epoxihydrolase. Knowledge on NAT
ontogeny is limited. NAT1 is lower in fetal samples as compared
to adults.108 Epoxihydrolase (EPHX 1 and 2) enzymes are decreased
at birth.34 These enzymes and NAT enzymes are not linked to major pathways in the metabolism of cytostatic drugs.
Renal excretion
Renal function in early infancy is severely diminished. In the rst
weeks to months of postnatal life, renal vascular resistance decreases and blood ow increases. Early after birth blood pressure
rises and induces a substantial increase in renal function. This is relevant for both glomerular ltration and tubular secretion during the
rst year of life.109 However, glomerular ltration reaches normal
values only from the age of 1 year onwards.110 Tubular drug elimination (transport and metabolic processes) is probably related to tubular immaturity of the kidney. It is assumed that normal tubular
function is fully developed by the age of 7 months.111 There are no
data on development of tubular function specic for the elimination
of cytostatic drugs.
Other general factors in infant cytostatic treatment
Many factors involved in expression or activation of enzymes
are only very partially known. In anti-cancer treatment, also in infants, the effect of co-administered drugs (among them dexamethasone and ketoconazole) are only partially known.112 This may be
very prominent in pediatric oncology patients who are treated
with several drugs during a prolonged period. An additional factor
of consideration in these patients is also forced diuresis during
administration of cytostatic drugs.113
Cytostatic drugs need to be divided in prodrugs and drugs
where the parent compound has cytostatic activity on its own. In
case enzymes are non- or low-expressed at birth a prolonged presence of the parent drug can be seen,2,113,114 whereas for prodrugs
this might lead to decreased serum levels of the active compounds
and but there will also be a longer formation of active metabolites.
However, also the decreased detoxication by the same enzymes
or enzymes in the same group might interact with the drug concentration. The nal results might be that the drug levels can be
relatively high and additionally the time of exposure can be longer.
Considering the changes in metabolic rate of enzymes, as based on
ontogeny, the scheme in Table 1 can be designed.
In this review this is only presented in detail for cyclophosphamide. Concerning cyclophosphamide, the enzymes CYP2A6, 2B6,
3A4/5, 2B6, 2C9 2C18 and 2C19 are involved in the metabolic step
to 4-hydrocyclophosphamide. But CYP3A4 is also involved in the
formation of chloroacetaldehyde. The low CYP3A4 levels might result in lower levels of chloroacetaldehyde and less 4-hydroxycyclophospamide, both resulting in less activity of the drug and less
toxicity related to the dechloromethyl-metabolite.115117 CYP 3A4

levels can exceed adult activity at certain time periods during infancy. As a result the balance of efcacy and toxicity is subjected
to substantial shifts.77 The relatively high levels early after birth
of CYP2B6 might promote cytostatic activity. And in the very rst
weeks after birth the decreased glutathione-S-transferase activity
might be causative for delayed detoxication of phosphoramide
mustard.21,32,40,118 This all illustrates that PK equipoise can vary
substantially in the early years of life, and can result in other risk
versus efcacy ratios.
Another point in drug metabolism is the polymorphic expression of enzymes involved in the different biotransformation pathways.119 Polymorphism might result in decreased activity of the
involved enzyme. Several enzymes involved show hardly any polymorphism; e.g. CYP3A4. Other enzymes, such as CYP2A6, 2D6, 2C9
and 2C19, are highly polymorphic.32 In adults it has been shown
that polymorphisms can lead to PK alterations and as a result in altered pharmacodynamic activity.120,121 The effect on moment of
expression and activation in relation to ontogeny for the various
subtypes is unknown.
A yet unknown factor in infant chemotherapy is the ontogeny of
drug transporters. In mice there is a limited expression of P-glycoprotein (P-gp) in the intestine at birth, however, levels of P-gp in kidney and liver showed adult values.122 In rat the amount of
expression of Multidrug Resistance Protein 2 (MRP2) is at birth
approximately 70% of adult values. After birth the expression of
MRP2 exceeds adult expression after 2545 days. In the female rat
higher MRP2 levels were found to peak at a later age.123 Studies on
m-RNA expression of MDR1, MDR2, and MDR3 in BALB/c and
C57BL/6 mice showed high variability among strains, among different organs and among age groups. An additional nding was that the
expression of various isoforms increased at older ages.124 Data on
ontogeny of drug transporters in man are very scarce.23,24 In respect
to absorption limited data exist for CYP3A4 and 1A1, which are lower expressed in the intestine at an younger age. This may result in an
increased absorption at a younger age.23,25 In the study of Stahlberg,
other detoxication enzymes have normal activity in normal intestine of pediatric patients. But in this study the number of patients
with normal villi at the age of 1 year (n = 8) was too low to make
any conclusive statements for this specic age range.23 Data on
developmental aspects of drug transporter enzymes within the body
and on those active in renal excretion nearly non-existing.
The differences in pharmacodynamics (PD) have been touched
upon earlier by mentioning the altered binding to target proteins
and aspecic binding to tissue protein. Also differences of expression of metabolic enzymes in the tumor cells themselves will inuence the effect of the drugs.125,126 As such overexpression of CYP1B1
was related to docetaxel insensitivity.127 To date hardly any study on
pediatric malignancies focus on expression of drug metabolizing enzymes. Altered PD can especially be caused by aspecic binding or to
differences in expression and avidity of membrane receptors. Another obstacle is the intracellular handling of drugs in relation to
the differences in disease characteristics per age.
In this review data on cytostatic therapy in children of less than
2 years of age are summarized, with a focus on data on children
<1 year. Studies were primarily selected if patients <1 year were
reported. If these patients were not available or only limited reports were found, studies on patients up to the age of 2 years were
included as well.
absorption with a higher dosage.128 With low doses (12 mg/kg)

there is nearly complete absorption of the drug.129 After oral
administration (36 mg/kg) the bioavailability is reported to vary
between 34% and 97%.128 Cyclophosphamide itself is an inactive
drug and its metabolism results in an array of active substances.
Cyclophosphamide is oxidized by several CYP450 enzymes into
4-hydroxy-cyclophosphamide. 4-Hydroxy-cyclophosphamide diffuses in the cell, but is not cytotoxic itself (Fig. 1). There is a direct
equilibrium of this compound with aldophosphamide. After
b-elimination of acrolein, phosphoramide mustard arises. The
acrolein metabolite is considered to be the product responsible
for urotoxicity. Several isoenzymes are involved in the metabolism,
including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19.50 CYP2B6
has the highest activity for the activation into 4-hydroxycyclophosphamide. In adults CYP3A4 is responsible for 10% and
CYP2C19 for 10% of its activation.53 Since phosphoramide mustard
from the plasma does not enter the cells, 4-hydroxy-cyclophospamide levels are suggested to reect the biological activity of
cyclophosphamide. In erythocytes higher concentrations of 4-hydroxy-cyclophosphamide than in plasma are found. Also activation
by CYP450 enzymes within the malignant cell has been suggested.
Additional activity is presumed to be related to acrolein. It possibly
enhances tumor cell kill by glutathione depletion.50,130,131 An alternate pathway leading to depletion of glutathione is the formation
of chloroacetaldehyde (with intrinsic cytostatic activity) via 2and 3-dechloroethylcyclophospamide directly from the parent
compound cyclophosphamide. This step is under control of
CYP3A4.132,133 Aldophosphamide can be detoxied into carboxyphosphamide.134 Cyclophosphamide resistant tumors can express
at a higher level aldehyde dehydrogenase enzymes, which are involved in this pathway. Activity of these enzymes can however
be inhibited by acrolein.135 Other processes involved in cyclophosphamide metabolism are e.g. conjugation with glutathione, aldose
reduction and alcohol dehydrogenation. In adults a very substantial amount (up to 80%) of cyclophosphamide is metabolized to
Alkylating agents
Cyclophosphamide
After oral absorption bioavailability of cyclophosphamide in
adults is dependent on the dosage used indicating a lower
Fig. 1. Metabolism of cyclophosphamide. The enzymes with highest activity are

depicted in bold.
carboxy- and ketophosphamide. Therefore only the aldophosphamide products escaping these oxidation steps can eliminate the
acrolein group to form the active phosporamide-mustard136 Elimination of the various compounds is performed by the kidneys. The
parent drug and its metabolites are excreted in the urine. However,
only 15% of the parent drug is renally excreted. A high intra- and
inter-patient variability in PK has been reported with serum half
life values (t) of 8.21 2.25 h.128 At higher doses kinetics are saturated resulting in prolonged half-lives.21,24,115 The half-life for
several of the metabolites are often shorter.50 Cyclophosphamide
is a potent enzyme inducer resulting in an increased clearance
after infusion on successive days.18,19 On the other hand, renal
insufciency results in a lower clearance of the drug.137
No data for oral administration in infants are available. Cyclophosphamide is in children, including infants, usually administered by intravenous route. From the data based on ontogeny of
metabolic enzymes and the data from literature the following effects in infants can be expected. Very young infants probably will
have a reduced production of dechloroethylcyclophosphamide,
based on the reduced CYP3A4 activity. This might result in more
substrate for the formation of the more active compounds and less
neurotoxicity, but increased urotoxicity. However the potential
formation of hydroxycyclophosphamide is regulated by CYP2A6,
which shows decreased activity as well. In respect to the aldophosphamide decay, one of the major metabolic pathways, the formation of carboxycyclophosphamide is decreased in infancy. This
will result in more substrate for the formation of phosphoramide
mustard, increasing cytostatic efcacy, and acrolein toxicity. After
a few months the activity of CYP3A4 can surpass the adults levels,
resulting in more dechloroethylcyclophosphamide what might
lead to less cytostatic activity but increased neurotoxicity.
To date there are limited data on age-related differences in concentrations of metabolites related to enzyme activity and cyclophosphamide metabolism. There are also no data on CYP450 activity in
pediatric tumor cells or intra-tumor phosphoramide mustard concentration. In children elimination half-life is substantially lower,
but inter- and intra-individual variability is high.138 Mean t values
of 1.484.86 h were reported in children ranging in age from 0 to
18 years.115117,139,140 A direct correlation was found for dosage versus t, although parameters such a volume of distribution and clearance were not correlated with t.115 Use of dexamethasone in
children resulted in a shorter t, which is in contrast to the use of
prednisone which caused a more prolonged clearance.115 Co-administration of azoles is related to prolonged t values due to inhibition
of CYP3A4/5.50,115 In a report by Yule et al. 5 children were below the
age of 1 year (range: 0.170.83 years) and 2 children were between
1 and 2 years of age. In this study t, volume of distribution and
clearance were not substantially different.115 No signicant
differences were reported for the AUC of cyclophosphamide and
its inactive metabolites dechloroethylcyclophosphamide and
4-ketocyclophosphamide, but a high inter-patient variation was
found for cyclophosphamide as well as it metabolites.116 Yule et al.
described in 36 children, ages ranging from 2 to 16 years with
non-Hodgkins lymphoma, a correlation between a prolonged t,
indicative of poor metabolism and activation of cyclophosphamide,
and higher levels of the inactive compounds carboxyphosphamide
and dechloroethylcyclophosphamide.117 In several other reports
only a very limited number of patients between the ages of 0 and
2 years were described. Differences in t and clearances of cyclophosphamide were not reported. With respect to cyclophoshamide
metabolism McCune et al. provided data on cyclophosphamide,
4-hydroxy-cyclophosphamide and carboxyethylphosphoramide
mustard (a non-toxic metabolite of aldophosphamide) in neuroblastoma patients (ages 1.309.37 years).141
For infants the following assumptions can be made: due to the
very limited renal function and enzyme immaturity in the rst
months of life substantial reductions are necessary. In addition

activation of metabolites might be strongly reduced as well as decreased neurotoxicity might be predicted based on decreased
CYP3A4 activity.
Ifosfamide
Ifosfamide has many similarities with cyclophosphamide. The
structure of the molecule differs mainly in the position of the chloroethyl moieties. The drug is metabolized in a similar way as cyclophosphamide, but for certain steps the rate of metabolism is quite
different. As a result, a higher dechloroethylation rate is noted
resulting in increased neurotoxicity. Both parent drug and metabolites are excreted renally, and due to the slower rate of activation
the amount of unaltered parent compound in the urine can be as
high as 50%.142 Ifosfamide is metabolized to dechloroethyl-ifosfamide, which is further degradated into chloroacetaldehyde, with
its neurotoxic effect.143 The metabolic pathway goes from 4-hydroxy-ifosfamide to aldoifosfamide into isofosforamide mustard,
which is in fact the cytotoxic compound similar to phosphoramide.
Ifosfamide has a longer half-life as compared to cyclophosphamide,
i.e. in adults 15 h in case of dosages of 3.85.0 g/m2. At lower doses
of 1.62.4 g/m2 the half-life is however the same as for cyclophosphamide.4143,144 Similar alkylating activity is found at substantial
higher dosages as compared to cyclophosphamide; 3.8 versus
1.1 g/m2.142 At lower dosages less inactive dechloroethyl-compounds are produced.145 In its metabolism distinctive differences
exist in the regulation by the various CYP450 enzymes as is also
seen in the metabolism of cyclophosphamide.146 CYP3A4 and
CYP2B6 are the major enzymes involved in the metabolism of
ifosfamide; both at the beginning of the metabolic pathway for
dechloroethylation as well as the formation of aldoifosfamide. In
contrast to cyclophosphamide the formation of the inactive
dechloroethyl metabolite (under control of CYP3A4 and CYP2B6)
is substantially higher (up to 50%).145 In addition about 25% is excreted unchanged in the urine.41,147 In contrast to phosphoramide
there is discussion whether extracellular ifosforamide mustard is
capable to enter the cell and elicit cytotoxic effects.148 Active compounds are in children able to pass the bloodbrain barrier, even in
higher concentrations as cyclophosphamide metabolites.
Similar to cyclophosphamide an increment in clearance rate is
observed after several days of infusion.149 In a pediatric study of
5 cases differences with respect to enantiomers were found, i.e.
mean t was 3.0 h for S-ifosfamide versus 4.5 h for R-ifosfamide.
No differential effect on auto-induction was noted for the enantiomers. Although S-ifosfamide has a greater efcacy, a greater toxicity and a higher therapeutic index when tested in ve in vitro
tumor models, the clinical relevance of these ndings in PK differences in children is not yet clear.150,151 Higher response rates in
adults were noted after bolus infusion as compared to continuous
infusion.152
Half-life in children is dependent on dosage. In children from 7
to 16 years t values ranges from 1.5 to 5.3 h using doses ranging
from 1 to 4 g/m2.147 In children bolus infusion resulted in a reduced production of dechloroethylated metabolites.153 In an Italian
study 1-h infusions resulted in more urological problems, whereas
patients on 24-h infusions had more neurotoxicity. This might be
explained by the saturation of CYP3A4 activity in respect to the formation of the dechloretylated metabolite. The urological problems
reect higher amounts of acrolein in infusions of short duration.
The resulting higher amounts of ifosforamide also explain the
higher response rate after bolus infusion in adults. Short duration
of infusion indeed proved to result in higher production of the
cytostatic ifosforamide mustard and the bladder toxin acrolein,
whereas prolonged transfusion results in the formation of the
non-cytostatic, but toxic 2- and 3-dechloroethyl-ifosfamide.153
10
Also administration at consecutive days resulted in lower concentrations of the parent drug but higher dechloroethylated metabolites, increased clearance and shorter half-lives. All phenomena
are indicative for auto-induction. This auto-induction is presumed
to occur very quickly, i.e. after 2 days it is apparent.153 Boddy et al.
compared bolus versus continuous infusion in 17 children; 4 of
them were below the age of 2 years. A boy of 0.8 years was the only
one younger than 1 year. Once again, it was shown that there was
up to 70% less of dechloroethylated metabolites in plasma following bolus administration compared to continuous infusion. No age
specic PK data were given.149 In another report of 16 children PK
of the parent drug, the carboxylated and the dechloroethylated
metabolites were investigated. Only 3 were below the age of
2 years (1, 1, and 1.9 year); no difference with the older children
became apparent.154
Based on the lack of data in infants it is hard to make conclusive
statements on the correct posology in infants. Very young infants
may experience increased cytotoxicity due to the lower activity
of CYP3A4 and the resulting lower levels of dechloroethyl-ifosfamide. Also the limited clearance by renal excretion and lower
ALDH may increase cytotoxicity. Whether less neurotoxicity during infusions of limited duration is seen in infants versus older children is doubtful. At an older age the activity of CYP3A4 is higher
and neurotoxicity may increase.
Mainly due to the limited renal function substantial dose reductions are advised in young infants.
Procarbazine, dacarbazine, temozolamide
Classical alkylating agents have a chloroethylgroup. In contrast,
drugs like procarbazine, dacarbazine (DTIC) and temozolamide do
not have such a group.
Procarbazine is a weak toxic prodrug. It is fully absorbed after
oral administration. The drug is readily distributed over the body
and equilibration of plasma and cerebrospinal uid is reached
within 15 min. Renal excretion is P75% in 24 h.155 Potential pathways of activation are chemical decomposition and oxidation in
the liver. The most probable way the drug exerts activity is the production of methyl- or benzylazoxy-intermediates which decompose into diazonium ions. However there is accumulating
evidence that production of O6-methylguanine is a very potent
mode of activity.156 Major steps in metabolism are under control
of CYP450 enzymes (1A and 2B) and MAO.41 Since the use of procarbazine in infants is extremely low, there are no data for this age
group. In infants dose reductions are to be advised based on the
limited renal function and slower metabolic pathways.
Dacarbazine (DTIC) has been developed as a purine anti-metabolite. There is high variability in absorption of the drug. This is in
humans a limiting step in the activation pathway. In contrast to
procarbazine, there is poor CSF penetration. The drug is excreted
in the urine, about 50% in unchanged form, and 20% as metabolites.
There is minor hepatic clearance.155 The action of the drug is however not via this pathway but by formation of monomethyltriazine-imidazole-carboxamide (MTIC), but also by generation of
O6-methylguanine.157 The last step is formation of the inactive
metabolite 5-aminoimidazole-4-carboxamide (AIC). Enzymes involved in the metabolic process are CYP1A1, 1A2 and 2E1.41 There
is a consensus how to relate the dosage to the glomerular ltration
rate. Similar to procarbazine there are no specic data for infants
available.
In infants dose reductions are to be advised based on the limited
renal function and slower metabolic pathways.
Temozolamide is another imidazotetrainone. In humans the formation of MTIC from dacarbazine is a limiting step for activation.
Temozolamide overcomes this problem by spontaneous decomposition under physiological circumstances into MTIC. This spontane-
ous decomposition is pH dependent. Increased turnover is noted at

a pH of 7.0. As a result decomposition may occur in the gastrointestinal tract in case acid production is limited, either mediated
by co-medication or due to age related low acid-production.14
After a further down step O6-methylguanine is formed. The last
step is formation of the inactive metabolite 5-aminoimidazole-4carboxamide (AIC). The drug is renally cleared.
In a study on 39 children with various tumors (median age
7.2 years, range 0.721.9 years) increase of body surface area and
age were linked with an increase clearance of the drug.158 An Italian trial comparing adults and children conrmed this nding.60
Based on 16 patients (median age 11 years, range 119 years) with
acute lymphocytic and non-lymphocytic leukemia it was concluded that pharmacokinetic parameters were similar to those
found in adults. However, there was a discrepancy between refractory and relapse patients, i.e. the O6-methylguanine-DNA methyltransferase (MGMT) was increased in the latter group. This might
be indicative for temozolamide resistance in these cases. Also in
a report on pediatric solid tumors low or absent MGMT activity
was related to the occurrence of a response. However there are also
reports contradicting this observation.147,159 No specic data for
infants are reported to date. For this group the following assumptions can be made. Due to the spontaneous degradation of temozolamide, dose reduction may be needed since accumulation of MTIC
may occur due to rate limiting steps later on.
In infants dose reductions are to be advised based on the limited
renal function and slower metabolic pathways. The lack of data for
procarbazine, dacarbazine and temozolamide in infants illustrate
once again that there is a need to collect PK data in as much children as possible. This is especially the case for the currently in
brain tumors very frequently used temozolamide.
ThioTEPA
The cytostatic effect of TEPA is the induction of DNA lesions. Two
major pathways of action of thioTEPA itself are probable. One pathway results in the binding of two DNA strands to the molecule. More
important seems to be the formation of aziridine, which crosslinks
with DNA. After infusion the drug is in part metabolized into TEPA
in a CYP450 catalyzed reaction. ThioTEPA is metabolized by the
same CYP enzymes (2B1, 2C11, 3A) as cyclophosphamide. Due to
inhibition of CYP3A4 by thioTEPA, metabolism of co-administered
cyclophosphamide is altered.32,160 The role of other metabolites
with alkylating potential such as non-chloroTEPA and TEPAmercapturate is still not fully claried.161 If given orally there is a
very rapid absorption. The mechanism of action of thioTEPA is not
fully claried. The drug is excreted renally.162
ThioTEPA is in childhood only used as intravenous solution. In
children >2 years of age undergoing bone marrow transplantation
with a conditioning regimen including thioTEPA PK data were
not different from the those in adults.163 In childhood dose-dependent PK were observed. Higher dosages of thioTEPA resulted in a
decline of plasma clearance and the increased formation of TEPA
seemed to be limited. TEPA had a longer half-life (4.35.6 h) than
thioTEPA, which has biphasic half-lives of 0.140.32 and 1.34
2.0 h. ThioTEPA is often used to treat brain tumors. Levels in blood
and cerebrospinal uid are nearly equal for both thioTEPA and
TEPA.66 Although thioTEPA is used in young children with brain tumors, no specic data for the age range <2 years could be recovered
from literature. By extrapolating the data on ontogeny of metabolism one might conclude that in very young infants a prolonged
exposure of the active TEPA, due to low renal function, can be presumed. Since both thioTEPA and TEPA are active compounds the
decreased conversion to TEPA, might not be relevant for posology.
Lomustine (CCNU) and carmustine (BCNU)

Both lomustine (CCNU) and carmustine (BCNU) belong to the
nitrosurea group. Their activity is largely dependent on the presence of a chloroethyl moiety, which decomposes to chloretylcarbonium. After splitting of the Cl-atom a binding with DNA is
established. DNA cross-linking occurs later on.164,165 Metabolism,
including activation, is dependent on rather unspecied CYP450
enzymes.166,167 The agents are rapidly absorbed and are lipophilic,
the volume of distribution is linked to body fat and serum fat content and the drug is renally excreted. No data in infants were
found. Related to the CYP450 dependency, a prolonged activity
might be possible in infants. In theory they run the risk that after
saturation of the normal pathway a higher concentration of toxic
alkylated metabolites might occur.167169 In infants dose reductions are to be advised based on renal excretion, higher serum values can be predicted due to low body fat and slow rate of
metabolism.
Chlorambucil
Activity of chlorambucil is similar to ifosfamide and cyclophosphamide based on the presence of an azidinium ring resulting in
alkylation and crosslinking of DNA, RNA and proteins.170 After oral
administration peak levels of chlorambucil are reached within 1 h.
The drug is metabolized in the liver and after administration of
radio-labeled chlorambucil over 50% of radioactivity is found in
the urine. In contrast to ifosfamide and cyclophosphamide metabolism into active compounds is not needed per se; although after
oxidation di-2-chloroethyl-2 (4-aminofenyl) acetic-acid-mustard
is an active metabolite. For the decay glutathione (GSH) and glutathione S-transferase (GST) activity are reported.41 No data on infants were recovered from literature. As a result activity of the
drug after allometric scaling in infants might result in increased
toxicity due to prolonged excretion of the drug and metabolite.
Busulfan
Busulfan belongs to the groups of alkylalkane sulfonates.
These react through binding to thiol groups of amino acids and
binding to guanosine. The cross linking of DNA capacity is, however, questioned. Busulfan has a high variable bioavailability. The
drug has a high penetration in the brain due to its lipophilic characteristics. The drug is metabolized by glutathione conjugation followed by oxidation.40 The role of glutathione-S-transferase
polymorphism with respect to busulfan conjugation is still debated.171 In the urine 3-hydroxysulfolane, tetrahydrothiofeen-1oxyde and sulfolane are recovered in the urine. Busulfan itself is
nearly undetectable in the urine.
The therapeutic index in children undergoing hematological
stem cell transplantation is however narrow. It was demonstrated
that an AUC of 78 mg h/l resulted in optimal event-free survival
rates. In case a high AUC is reached the risk for graft-versus-host
disease increases.172 Lower Cmax values were related to a higher
risk for sinusoidal obstruction syndrome (formerly called venoocclusive disease) of the liver.173 Inter- and intra-patient variance
of blood concentration is signicant.174,175 It has been shown that
in busulfan the half-life elimination decreases substantially; from
3.4 h after the rst dose to 2.3 h. A major difference in t in subsequent courses has also been described for children with leukemia
versus those with inherited diseases; 3.16 and 2.7 h versus 1.93
and 1.71 h, respectively.176 Although these changes in PK might
be related to enzyme induction, others deny such alterations related to sequential administration.177 One of the most extensive
studies in the very young age group has been reported by Nakamura et al. They examined 1028 samples from 103 children with a
11
median age of 18 months (range 2 months to 11 years).178 They reported the peak of highest clearance at 24 months of age.
In a single study PK parameters were collected from 46 children
(median age 3.0, range 0.2516.2 years). Mean volume of distribution at steady state was larger in children <4 years of age than in
older children. Total body clearance was not different for the various ages. However, compared with older children, mean weightadjusted clearance was higher in children <4 years of age
(3.8 1.40 versus 3.0 0.76 mL/min kg).80 Modeling studies suggested that oral clearance expressed per kilogram of body weight
is low in early infancy. Clearance increases to a maximum at
approximately 2 years of age, but decreases later on.62 Despite differences in clearance Vassal et al. were able to achieve for all children acceptable AUC if dosing was performed according to weight
strata: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for
1623 kg; 0.95 mg/kg for >2334 kg; 0.80 mg/kg for >34 kg.179 This
is in line with ndings from Schechter et al. and was related higher
GSTA11 expression in the intestinal wall in young children.173,180
To limit at least the variability in absorption the intravenous
formulation is currently often used. In a recent study investigating
intravenous busulfan in 24 children (including three in the age
range from 0.4 to 0.6 years and ve in the range from 1.1 to
1.9 years) no signicant differences in clearance were found in
relation to age. However, this study supports the nding by Dale
et al. to use lower dosages in infants <10 kg.181 Dalles report gives
data on 14 infants below the age of 1 year. They advise a starting
dosage of 0.8 mg/kg followed by adjustments based on PK
determinations.174
Melphalan
In children melphalan, an alkylating agent, is only used in conditioning prior to stem cell grafting. It is only administered intravenously. When given orally, melphalan absorption from
gastrointestinal tract is highly variable.182 The drug is for 7080%
bound to plasma proteins and is metabolized in the liver into
monohydroxy-melphalan and dihydroxy-melphalan. After the formation of carbonium metabolites the two bis-2-chloorethyl groups
bind covalently to guanine and induce DNA cross-linking. Further
metabolism results in mono- and bishydroxyethyl products with
no cytostatic activity. Elimination half-life in adults is about
1 h.183,184 Renal clearance is hardly important considering the limited excretion in the urine (about 1015%).185,186
Goyette et al. compared PK in adults and children and their
ndings showed similarity. Of the 20 children only one child was
below the age of 2 years (1 year 10 months). There was a difference
for those children who were on furosemide treatment and those
not on furosemide, indicating that those on furosemide had a lower
plasma clearance.113 In case of the simultaneous use of carboplatin,
lower doses of carboplatin are needed to achieve a similar AUC.
These data on the combined use were derived from a modeling
study incorporating 59 children with an age range of 0.318 years.
The number of patients below the age of 2 years could not be
recovered from the report. Covariates included in their models
were weight, carboplatin use and glomerular ltration rate.187 Also
total body irradiation was found to be a factor in melphalan clearance.188 No statements on dose recommendations can be made in
infants based on these reports.
Antimetabolites
Cytosine arabinoside (Ara-C)
After oral administration only a small fraction of Ara-C is absorbed. As a consequence, this drug is given intravenously or sub-
12
cutaneously. Protein binding is limited and as a result the distribution volume is 0.7 l/kg; Ara-C doesnt penetrate the bloodbrain
barrier. It must be converted through a cascade of phosphorylation
reactions into Ara-C-triphosphate (ara-CTP), which blocks DNApolymerase activity and ribonucleotide reductase, and most
importantly it is incorporated into the DNA.189 For entry in the cell
the nucleoside transporter 1 (hENT1) is needed. The rate limiting
step in the activation pathway is the intracellular saturable enzyme cytidinedeoxy kinase (cDK). It has been found that Ara-CTP
levels are higher in leukemia cells as compared to normal lymphocytes.190 PK and pharmacodynamics are inuenced by the type of
leukemia. Both cDK and hENT1 can be different for the specic leukemia cells and the stage of the disease. A metabolite of Ara-C is
Ara-U; which is not further phosphorylated and not incorporated
in DNA. Plasma Ara-U inhibits Ara-C deamination and by this enhances Ara-C activation.191 The half-life of Ara-C is 720 min. The
metabolites (mainly Ara-U) are renally excreted, and only 10% is
excreted as Ara-C.
In leukemia cells in children the activity of cDK is the rate
limiting step. Avramis et al. described in 8 children (age ranges
0.7516 years) that cDK activity is similar to the activity found in
adults.192,193 The rate of conversion of Ara-C to Ara-U has however
a linear relation with patient age. This results in an increased Ara-C
clearance observed in older children as compared to infants.194 In
infants with ALL a 2-fold lower level of cDK-mRNA, but a 2.5-fold
higher mRNA of hENT1, responsible for Ara-C membrane transport
has been described. The mRNA expression of hENT1 was found to
correlate inversely with in vitro resistance to Ara-C. An oligonucleotide microarray screen comparing patients with mll- generearranged ALL with those patients with non-mll-rearranged ALL
also showed a 2.7-fold higher hENT1 mRNA expression in patients
with mll- gene-rearranged ALL (p = .046). This probably explains
the high sensitivity in infant ALL to Ara-C.195 Also other factors
such as concomitant medication and characteristics of the malignant cells can result in changes both in extra- and intracellular
pharmacokinetics. For example, administering Ara-C after udarabine, augments in children the intracellular Ara-CTP levels.196 In a
study on 3 infants (0.640.9 years) median systemic clearance was
not different from 64 children of older age (119 years).197 The
general advise to decrease dosages with 50% is therefore not supported by the available pharmacokinetic data.6 As can be concluded from data mentioned above, statements on PK in infants
are hard to predict. Data on the age-related differences in activity
are partly known and especially in the induction phase of remission differences related to the metabolism of the malignant cells
probably play a major role.
Gemcitabine
Gemcitabin is given only intravenously. The drug is metabolized
in the liver, kidney, blood and other tissues. Like Ara-C, gemcitabine has to undergo intracellular phosphorylation by DCK into active diphosphate- and triphosphate forms. The penetration into the
cell is substantially higher than Ara-C and the same holds for intracellular retention. The anti-tumour activity differs from Ara-C and
is broader.198200 The killing effects of gemcitabine are not conned to the S-phase of the cell cycle. The diphosphate substrate
is an inhibitor for ribonucleotide reductase resulting in depletion
of the nucleotide pool and it makes, after incorporation into the
DNA, the cells resistant to DNA repair enzymes.199,201,202 This effect
has been shown to enhance the cytotoxic effect of concomitantly
given other cytostatic drugs. Metabolites are excreted renally and
represent over 90% of the administered drug. PK data in children
were reported by several authors. However, the youngest child
was already 2 years at study entry.203205
Methotrexate
Methotrexate is the most common used antifolate. Mode of action is inhibition of dihydrofolate reductase leading to depletion of
reduced folates, which interferes with purine metabolism. This is
not the single way methotrexate exerts its activity. Methotrexate
is converted to polyglutamates in both the liver and intracellularly
in various tissues/cells. Polyglutamated dihydrofolate and 10formyldihydrofolate metabolites are potent inhibitors of thymidylate and purine biosynthesis.206,207
Methotrexate is absorbed from the gastro-intestinal tract by
means of a saturable active transport system, resulting in lower bioavailability at high dosages. After entry of the portal vein, the drug is
polyglutamated and stored in the liver. Distribution approximates
total body water. Penetration to the central nervous system is not
sufcient to reach adequate levels for kill of malignant cells. Methotrexate (and Ara-C) are the standard drugs given intrathecally. Based
on the distribution of volumes in the subarachnoidal space; which
are highly age dependent, specic age related dosages are applied.
Methotrexate is metabolized into 7-hydroxy-methotrexate by aldehyde oxidase in the liver. This product can be polyglutamized in the
liver. However, only a small percentage of methotrexate is metabolized into 7-hydroxy-methotrexate. This enzymatic step is more active at younger ages as can be concluded from higher concentrations
of the metabolite.208 This metabolite is excreted in the bile, but in
high dose methotrexate treatment, it is found in the urine as well.
Bile excretion is inhibited by simultaneous administration of dactinomycin, folic acid, 5-methyltetrahydrofolate, rose Bengal, sulfobromophthalein, deoxycholate and conjugated taurocholate salt,
which is indicative for an active drug transport. There is enterohepatic reabsorption of methotrexate. Another metabolite is DAMPA,
which is probably formed by bacterial carboxypeptidase in the gut.
As mentioned earlier two modes of action are assumed, i.e.
anti-folate activity and polyglutamation. Which of both cytotoxic
mechanisms are most relevant remains unresolved up to date. The
suggestion that the favorable prognosis of leukemias harboring
the TEL-AML1 translocations is correlated with the higher concentrations of polyglutamates is tempting.209 Whether the poor prognosis in infants with ALL is related to methotrexate insensitivity is
still unsettled. Polyglutamates can reside in the cells and be active
for a prolonged time. The time these compounds exert their action
varies between various tissues and malignant cells. Concomitant
administration of other cytostatic drugs can signicantly change
the PK of methotrexate. For instance simultaneous administration
of Ara-C induced methotrexate levels in erythrocytes, that were only
a fraction of the levels in concomitant use of Ara-C.210 Simultaneous
administration of etoposide increases methotrexate levels in the
blood signicantly.211 The drug is excreted in the urine; the amount
of excretion is dependent on the dosage. With the use of lower dosages excretion percentages as low as 44% are found, whereas with
high dose therapy, nearly 100% of the drug is renally excreted. Renal
excretion occurs both through glomerular ltration as well as tubular excretion of unaltered methotrexate. Part of the methotrexate is
re-entered due to tubular absorption. Alkalinization of the urine
inhibits tubular reabsorption. Elimination half-life depends on the
doses given. For adults treated with low dose methotrexate 310 h
and for high dose 815 h has been reported. Decrease in renal function results in lower clearance rates and increased toxicity.
PK in ALL revealed increments in methotrexate clearance from
the rst 3 months after birth (84 30 ml/min/m2) onwards to even
160 71 ml/min/m2 in adulthood.197,212214 High clearance rates
were already reported in the age range 13 years.214 Comparing
children of less than 10 years of age versus older children a
decreased clearance in the older age cohort has been reported.214
A study specially focusing on infants (n = 103) reported that
clearance tended to increase with age in these infants, and that
boys had higher clearance rates than girls, 6.77 and 5.28 L/h/m2
(P = 0.030).215 As a consequence, it can be concluded that clearance
increases during the rst year of life, but declines thereafter. The
decrease in hydroxylation at an older age, as described by Borsi
et al. may be an explanation for this decrease later on.208 In a study
of 16 infants (2 months to 1 year) dosage dependent clearance was
suggested with signicantly lower clearances at higher dosages.
The authors propose allometric dosing schemes using body surface
adjustments.197 Data on the levels of methotrexate-polyglutamates in infants are rare. In the study of Ramakers-van Woerden
et al. levels are lower in the 8 children below the age of 1 year,
but ndings did not reach signicance. The authors do not link
methotrexate resistance with alterations in metabolism.216 Similar
to the situation in Ara-C efcacy this nding is probably related to
the type of leukemia.
Pemetrexed
Pemetrexed is a novel antifolate inhibiting the biosynthesis of
thymidine and purine nucleotides, targeting at thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide
formyl transferase.217,218 Following intravenous infusion, it is also
polyglutamized. After cell entry a prolonged retention and enhanced
target interaction is claimed. As such a greater efcacy as compared
to methotrexate is assumed.219,220 The drug is excreted renally. The
role of this antifolate in pediatric oncology is still under discussion.
The drug was well tolerated in a study of 31 children (age range 1
21 years; median age of 12 years with refractory solid tumors.221
6-Mercaptopurine
6-Mercaptopurin is the most often orally prescribed drug. Other
forms of administration are rectal and intravenous; and for both
the rst pass effect is absent and systemic exposure is substantially
higher.222 6-Mercaptopurin (6-MP) is a structural analog of hypoxanthine. Bioavailability of 6-mercatopurin is highly variable. Following oral dosing dosing bioavailability is only 537%.223 This is,
however, not related to absorption, but is a consequence of very
early decay of the drug, due to high activity of xanthine oxidase
in the intestinal wall. The distribution exceeds total body water
(i.e. 0.9 l/kg). Concomitant use of allopurinol gives a steep increase
in bioavailability.224 Increasing the oral dosage results in a disproportional increase in bioavailability indicating a saturable rst pass
effect.225 Several metabolic routes occur. One of the most important ones is intracellular activation into 6-MP ribose phosphate,
which inhibits de novo purine synthesis. 6-MP also converts to
6-MP ribose triphosphate, which is incorporated in DNA and
RNA. It was shown that cytotoxicity is best correlated with the
quantity of 6-MP metabolites incorporated in the DNA.226 6-MP
is cleared from the body by oxidation into inactive 6-thiouric acid
by xanthine oxidase and methylation by thiopurine methyltransferase (TPMT) into 6-methylMP. Since there is no negative correlation between levels of methylated forms and 6-thiouric acid, there
are probably more modes of decay of the drug. The decay of 6-MP
by TPMT activity is subject to genetic polymorphism.227 Several
variants have been described; TPMT3A, TPMT3B and TPMT3C
being the most important ones to consider. TPMT3A is the most
common variant allele in Caucasian subjects (frequency approximately 5%), TPMT3C is the most common variant in East Asian
subjects (frequency approximately 2%). Single-nucleotide polymorphisms (SNPs) have been sorted out for these variants. In both
TPMT3A and B there is an Ala254Thr alteration. In TPMT3A and
TPMT3C Tyr240Cys is the (for TPMT3A additional) alteration
found. Both TPMT3A an TPMT3B result in virtual lack of enzyme
activity. The decrease in activity in case of a TMPT3C variant is less
pronounced.228,229 In homozygous TPMT3A patients very substan-
13
tial dose reductions are needed. In heterozygous patients reductions are often intermediate.230 ALL patients with high TPMT
activity and/ or a wild type TPMT gene are prone to a higher risk
of relapse.231 There is renal elimination of the metabolite thiouric
acid, whereas less than 10% of the drug is excreted unaltered in
the urine. Excretion is different for intravenous versus oral administered 6-MP. In children 21% of unaltered 6-MP is found in the urine after intravenous administration versus only 7% after oral
ingestion. In case of concomitant use of allopurinol 42% urine
excretion has been documented.232 Due to the high inter-patient
variability of metabolism (especially in relation to TPMT activity)
in clinical practice white blood cell counts are used as surrogate
marker for adequate dosing. Kinetic studies are sparse. In a study
of 3 infants (0.581 year) the variability in metabolites was substantial and comparison with 103 older children did not reveal statistical signicant differences.197 Balis et al. included patients with
ALL in the age range from 1.1 to 17 years of age and observed no
age related changes in blood levels.233 Since 6-MP is mainly used
in maintenance treatment of malignancies; dosing is performed
according to white blood cells values. As a result the alterations
in dosing according to age (and in according to TPMT activity)
are in fact covered by these dosing adjustments.
6-Thioguanine
6-Thioguanin (6-TG) is closely related to 6-MP. Both drugs are
mainly used in the treatment of leukemia. 6-TG has quite similar
mode of action and metabolism as 6-MP. It is however more directly converted into thioguanine nucleotides. Bioavailability of
6-TG is variable; variations between 14% and 46% are reported.
CNS penetration is similar to 6-MP and using continuous infusions
intrathecal cytotoxic drug levels can be achieved.234 6-TG gives
lower peak plasma concentrations in comparison with 6-MP. Some
studies report a higher susceptibility of in vitro leukemic cells for 6TG.235,236 Metabolism differs from 6-MP, since 6-TG is not a substrate for xanthine oxidase, but it is converted into the active
metabolite 6-thio-inosine by guanase. As a result allopurinol
doesnt block degradation as is the case with 6-MP. TPMT induced
methylation is more extensive than 6-MP, but that product is less
active then 6-TG itself. Since no thiouric acid is formed due to absence of the xanthine oxidase mediated step, there is mainly hepatic clearance of the drug. Less than 10% of the drug is excreted
unaltered in the urine.
Studies comparing 6-MP and 6-TG in children with ALL, showed
that the main metabolites of 6-TG were thioguanine nucleotides,
whereas during 6-MP treatment methylated thioinosine nucleotides predominated. Levels of methylated thioguanines were even
26-fold higher. The median thioguanine nucleotides concentration
was about 7-fold higher in the thioguanine branch. In contrast to 6TG, the pattern of metabolites administering 6-MP shifted toward
the methylated ones with increasing dose.237 In a randomized
study there was no difference in outcome in children on 6-MP versus 6-TG.237 In another study comparing 6-TG and 6-MP, 2027 patients with acute lymphoblastic leukemia were randomized.238 A
signicantly higher EFS (84%; versus 79% for 6-MP) was found;
however, overall survival was similar 91.9% and 91.2% respectively.
In the 6-TG group 25% of patients developed a sinusoidal obstruction syndrome and these patients were switched to 6-MP treatment. Similar to 6-MP drug dosage is based on white blood cell
count during therapy. In a comparison of Down-syndrome children
(median age 1.8 year; range 1.13.3 years) versus non-Down
syndrome children with acute myeloid leukaemia (median age
11.0 years; range 0.517.7 years) the administered dosage of
6-TG was substantially higher in the latter group. The same
authors also compared the amount of drugs given to non-Down
children <2 years of age (n = 5) versus the 35 children above that
14
age. The total dosage needed to achieve comparable blood levels

was about 75% of the dosage given to older children.239 However,
the relevance of determining blood concentrations can be
questioned since 6-TG concentration was in both univariate and
multivariate analysis not an independent factor for CR.239 Similar
to 6-MP, dosages are titrated on basis of leukocyte counts. There
are no data specic for infants.
5-Fluorouracil
After intravenous administration 5-uorouracil rapidly penetrates the extracellular space and the cerebrospinal uid. The
volume of distribution exceeds slightly extracellular uid space.
Fluorouracil is in the cell activated through formation of 5-uorodeoxy-uridine-5-monophosphate and 5-uorouridine-5-phosphate. It exerts its action at the moment it is incorporated into
RNA. The drug further inhibits thymidylate synthetase. To a lesser
extent it is incorporated into DNA. Decay of the drug takes mainly
place in the liver. Fluorouracil is often used in adults in combination with leucovorin in order to enhance activity.240 Excretion is
almost completely via the hepatic route.
Currently instead of uorouracil its prodrug, cepacitabine, is often used. Both uorouracil and cepacitabine are seldomly used in
pediatrics. A phase 1 trial, including 35 evaluable patients (median
age 9 years; range 121 years) with refractory malignancies, conrmed applicability of similar dosage of uorouracil in children
as in adults. In respect to the concomitant used leucovorin, the
total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid were approximately the same as in adults,
even though the Cmax of each compound was lower.241
CYP2A6 is a major enzyme in 5-uorouracil metabolism and
enhances the activation of the prodrug tegafur.49 As a result if ever
5-uorouracil treatment in infants is indicated, this orally taken
prodrug is not a good choice.
Fludarabine
Fludarabine is only given by the intravenous route and is quickly
metabolized. Peak values of the dephosphorylated metabolite are
reached within 30 min. Elimination is for 4060% via the renal route.
In animals radioactivity after labeling of the drug was fully recovered from the urine. Fludarabine is the monophosphate analog of
adenosine-arabinoside. After infusion it is fully dephosphorylated.
In this form it enters the cell and it is phosphorylated into udarabine triphosphate. There are indications that udarabine is also able
to inhibit RNA polymerases and depletion of nicotinamideadeninedinucleotide, which results in decrease in cellular energy stores and
interferes with the DNA repair process.242244 As a result the activity
of udarabine is not limited to the S-phase. Due to the depletion of
deoxynucleosides due to inhibition of ribonucleotide reductase
there is a decreased inhibition of cDK, which results in case of
co-administration of Ara-C in augmented Ara-CTP levels. There is
linear renal clearance and 5060% is recovered in the urine, whereas
no metabolites are detected.245 In children the terminal half-life was
similar to adults, while the total body clearance was shorter than
reported for adults receiving bolus or continuous doses.246 In 31
patients (median age 8 years; range 119 years) cellular Ara-CTP
levels augmented 58-fold in leukemia cells from patients receiving
udarabine phosphate treatment followed by Ara-C.246 No specic
infant data are available.
Cladribine
Cladribine is usually administered intravenously. After subcutaneous administration there is 100% bioavailability. Intracellular
concentrations were found to be several hundred-fold higher than

plasma concentrations.
Cladribine is a chlorinated adenine analog. After cell entry it is
phosphorylated by deoxycytidine kinase. In cells with a high content of deoxycytidine kinase the metabolites are incorporated in
DNA inducing strand breaks. There is further inhibition of ribonucleotide reductase, which is an additional negative factor for DNA
synthesis and repair.247,248 Fifty percent of the drug is eliminated
by renal excretion.249 In a pharmacokinetic study of 25 (mostly
pediatric) patients (median age 9.6; range 0.723.3 years) it was
shown that clearance per body weight was lower in older children,
but after correction according to body surface the differences disappeared.250 A study in 49 children (median age 9.8 years; range
0.420.2 years) on the simultaneous administration of Ara-C and
cladribine showed an increase in intracellular Ara-C metabolite
concentration. The clinical relevance of this nding is, however, debated.251 As with other cytostatic drugs, who are actively transported the (malignant) cells, pharmacokinetics, but especially
pharmacodynamics are hard to generalize for infant malignancies.
Dosage adjustments should e related to renal function because of
the important role of renal function in clearance of the drug.
Antimitotic drugs
Vinca alkaloids
The primary mode of action of vinca alkaloids is the interaction
with tubulin, but other effects are noted as well; such a competition for amino acid transport into the cell, inhibition of RNA,
DNA and protein synthesis, disruption of lipid metabolism, increase of oxidized glutathione, inhibition of glycolysis, altered release of antidiuretic hormone, inhibition of histamine release,
augmented adrenaline release, inhibition of calciumcalmodulinregulated cAMP-phosphodiesterase and disruption in the integrity
of the cell membrane and its function.252254 The effects on tubulin
interruption vary with age.255 Dosages of the various alkaloids are
different. Vinca alkaloids have to be administered by the intravenous route in infusions, only vinorelbine can in children be given
in an oral formulation.256258 Bioavailability of the oral formulation
is however only 2540%.259,260 Vinca-alkaloids have quite similar
PK characteristics, with a tri-exponential prole of clearance. Volumes of distribution are large and there is high tissue binding.
Intracellular concentrations are substantially higher than plasma
levels. CYP 3A4 is one of the enzymes involved in the metabolism
of vinca alkaloids.261,262 A terminal t up to 84 h reported for vincristine. Clearance for all products is hepatic, resulting in biliary/fecal excretion. Side effects differ among the various alkaloids.
Studies in children revealed high inter-patient variability in PK.
In a study on vincristine monotherapy, the clearance was substantially lower as compared to children who were on steroids. This
observation is very important for children because corticosteroids
and vincristine are the main component of anti-leukemia therapy
The inter-patient variability is not fully explained, but for the differences in children receiving steroids versus those not on steroids
the induction of CYP3A4 by steroids may be explanatory.112,263266
Whether this induction is seen in infants is unknown. There is a
difference in metabolism of vincristine with respect to characteristics of the malignancy. Hyperdiploid (with >50 chromosomes) leukemia patients showed a faster clearance of vincristine as
compared to diploid or hyperdiploid (4650 chromosome)
cases.263 In infancy leukemia with hyperdiploidy >50 chromosomes is not a prominent subtype. Since, hyperdiploidy >50 chromosomes is a factor correlated with better outcome, the relation of
PK of vincristine versus outcome remains to be claried.267,268
Neuropathy could not be related to PK parameters.264 In children
above the age of 1 year some relation of younger age and lower
clearance is suspected, but in multivariate analysis this seemed not

to be signicant.265 Similar observations were done by others.269 In
infants <1 year only limited data are available. Crom et al. reported
on vincristine use in two 2 months old infants, and they found that
when clearance was normalized to body surface area, the clearance
in these infants was much slower than in older children. If normalized for body weight the clearance approached the ndings of older
children 16.7 versus 20.6 ml/min for children 210 years of age.264
Based on these ndings posology should be based on weight,
rather than a simple decrease by 50% on top of dosing according
to body surface area as used in literature.6
Taxanes
Taxanes are given by intravenous infusions. Oral administration
is possible, but only in conjunction with oral modulators of ABC
transporters (e.g. cyclosporine) and/or cytochrome P-450 mixed
function oxidases to decrease the effects of rst pass absorption
and metabolism in the intestine and liver. Taxanes bind to all tissues,
except for the central nervous system tissues. This results in large
distribution volumes and a short distribution t and protracted terminal t values. Elimination is though the hepatobiliary system.
Paclitaxel: Primary mode of action is binding to the microtubules.
As a result there is bundling of microtubules within the cells, resulting in a mitotic block at the metaphase-anaphase of the cell. Paclitaxel is less potent than the related docetaxel.255 Paclitaxel is
metabolized by CYP450 (mainly 2C8 and 3A4) and excreted in bile.41
One of these products is 6-alpha-HO-paclitaxel; a metabolite with
only very limited cytostatic potential.270,271 The parent compound
is a minor part of the drug excreted. There is a negligible penetration
in the central nervous system.270,272 Data in children are scarce; and
for infants hardly any data are available.271,273,274 In the phase I
study of Doz et al. 17 patients were included with an age range of
1.619 years (mean 9 years).275 The phase I study of Horton et al.
was done in 63 patients with an age range of 0.823 years.276 Major
side effects are hematological toxicity and hypersensitivity. Peripheral neuropathy is the most limiting factor for use in children.275
Data on docetaxel are even scarcer. Docetaxel is metabolized to
inactive oxidation products, mainly by the CYP3A4/5.41 The metabolic activity is inuenced by polymorphism of these genes.277 In
the report of Franklin et al. from the Childrens Oncology Group
(COG) 12 children with leukemia were included (mean age 6 years,
range 121 years).278 A study on solid tumor pediatric patients included only patients from the age of 2 years onwards.279
For infants dose recommendations on the use of taxanes cannot
be made.
Topoisomerase inhibitors
In humans 3 topoisomerase families are known.280 Topoisomerase inhibitors exert their action through transesterication, in
which a phosphoester-bond is transferred to a specic enzyme
generating breaks in the DNA backbone. Type 1 enzymes make
breaks in single stranded DNA, type 2 enzymes make breaks in
double-stranded DNA. As a result of both the replication of DNA
is interrupted. The currently used inhibitors, etoposide and teniposide, belong to the type 2 family. The camptothecans (topotecan,
irinotecan e.g.) belong to the type1 family. Although many cytostatic drugs have topo-isomerase activity, e.g. anthracyclines and
actinomycin, their activity is not specic enough to be categorized
among topoisomerase inhibitors.281
Etoposide
In children etoposide is given by intravenous infusion. Oral
administered etoposide has a highly variable bioavailability, and
15
in pediatrics it is only used in palliative settings. After infusion etoposide is for >90% bound to plasma proteins. There is hardly any
penetration in the central nervous system. Etoposide is metabolized into several products, with the major product being
etoposideglucuronide. A metabolite with cytotoxic activity is
the O-demethylated one, which is formed in the liver. CYP3A4 is
an important enzyme for the conversion into this product.282 Most
metabolites are broken down into quinones. This is probably under
the inuence of CYP3A5 activity. Other enzymes involved in the
metabolic process are CYP1A2 and 2E1.41,277 Concomitant medications such as steroids and anti-epileptic drugs, do inuence PK due
to induction of CYPs.112 Elimination is by hepatic clearance, about
one third of the drug/metabolites is cleared by the kidney.
Despite the fact that the PK in children of various ages is quite
similar, dosing according to the body surface area has been shown
to result in 8 out of 33 cases to either under- or overdosing of the
drug.283287 The authors showed that only an equitation introducing peak level, duration of infusion time and a Cr-elimination rate
constant predicted the AUC appropriately.288 In a study including 4
children ranging in age from 0.5 to 1.8 years the clearance rate was
not substantially lower than in older individuals.283 Observations
in 2 infants (0.5 years and 1 year of age) suggested that systemic
clearance increases with age. In the same report children >1 year
were also assessed. In these older children no relation of age and
clearance was found.197 In a recent report on the combined use
of carboplatin and etopside in 19 children with 4 below the age
of 6 months and 13 below the age of 13 months, an equation relating clearance to body weight was formulated.287 These data appear
sound for children above the age of 6 months; however, in the very
young infants the limited glomerular ltration rate may require
further prudence.
Teniposide
Similar to etoposide there is a variable bioavailability after oral
administration, i.e. smaller dosages have higher bioavailability.
After infusion teniposide is highly bound to plasma proteins
(>99%) resulting in a high volume of distribution. There is hardly
any penetration in the central nervous system. A limited amount
of the parent compound is excreted in the urine.289 Enzymes involved in the metabolic process are CYP3A4 and 3A5.41 Major
metabolites in children are hydroxic acids.290 Elimination is by hepatic excretion, but after 140 h about 45% of radioactivity of radiolabeled teniposide was recovered in the urine. There is an inverse
correlation between ALAT levels and clearance of the drug, indicative of metabolism in the liver. Excretion in the faces is limited
(about 10%).
In a pediatric study of children ranging from 4.86 age onwards,
t was 8.95 3.73 h, which is a bit shorter then reported in adults.
However, t was dose independent.281,291 In a study including 6
pediatric patients, no age specic PK differences were mentioned
(the youngest being 3.7 years).292 In a study on 3 infants (ages
0.640.87 years) normal clearance rates were found. As a result
normal dosing based on body surface was advised.197 In young infants below 6 months dose reductions seem sensible, however no
specic guidance can be given on basis of limited data.
Topotecan
Topotecan can be administered both orally and intravenously.
Oral administration is highly variable due to the effect of drug
transporters, food and high pH in the bowel, leading to conversion
to the carboxylate form. Bioavailability after oral administration is
only 3550%.293 Addition of inhibitors of drug transporters results
in an increased bioavailability. Adding drug transporters inhibitors
results in increased bioavailability. Penetration of the central
16
nervous system gives levels of about one third of the systemic levels. After absorption the lactone ring of topotecan undergoes rapid
hydrolysis and carboxylate derivatives are formed.294 Involved in
this process is probably CYP3A4.41 These carboxylate derivatives
have no cytostatic activity; since an intact lactone ring is essential
for the interaction with topoisomerase1.293 Eighteen percent of
intravenously administered topotecan is found in the feces. In
pediatric studies 90% of the product and carboxylate derivates
could be recovered from the urine (2550% within 24 h).295,296 In
the urine also a O-glucuronidation metabolite and a N-desmethyl
metabolite were recovered.297,298
Biliary excretion is limited and is not very effective for ultimate
excretion from the body due to enterohepatic recycling.293,299,300
Elimination half-life t of the parent drug ranges from 1.6 to
5.5 h. Median t after oral administration was 4.1 h.301
Studies in children have not indicated any differences in pharmacokinetics as compared to adults.295,302310 In the studies of
Athale et al., Blaney et al., Frangoul et al., and Santana et al. a number of children of 1 year of age were studied. However, the exact
number of these infants remains uncertain.302,303,305,307 Panetta
et al. developed a PK model in neuroblastoma patients as young
as <1 month. Median age of the group assessed for modeling was
3.1 year. They felt no need for inclusion of age as factor.311 However, in the description of another modeling experiment by the
same group of researchers an age <0.5 years was a covariate in case
age was used as a categorical factor.312 Based on these ndings and
based on data on ontogeny additional dose reduction in infants are
advised.
Irinotecan
Irinotecan is usually administered intravenously. Despite the
large distribution volume, the penetration in the central nervous
system is nearly absent, but its metabolite idarubicinol penetrates
the bloodbrain barrier, and CSF levels approach those reported as
being cytotoxic to human tumor cell lines.313 Irinotecan is a prodrug requiring enzymatic cleavage by carboxylesterase converting
enzyme to form the active metabolite SN-38. Both the parent drug
and SN-38 undergo reversible hydrolysis of the lactone ring.314
Other enzymes inuencing metabolism are 1A3, 1A7, UGT1A9,
1A10 and ABCC2.41,315 Elimination half-life of SN-38 (8.7 h for
SN-38) is substantially longer then for irinotecan.316,317 Additionally irinotecan undergoes oxidation via CYP3A4 and 3A5 to relatively inactive, but toxic metabolites. One of these metabolites
can be converted to SN-38 by carboxylpeptidase.41,318,319 SN-38
is primarily glucuronidated and inactivated by UGT1A1 and excreted in the bile. In addition there is enterohepatic circulation.320
About a quarter of the parent drug is excreted in the urine.
A few reports on PK provide data in children. From 3 studies
done by the COG it becomes apparent that children below the
age of 10 years have an increased clearance of SN-38. Although
not a linear correlation was described, the graphs show a clear
increment at the younger ages. The authors sought an explanation
in the higher ratio liver versus body weight. Other factors, however, may be important as well; such as an altered enterohepatic
circulation and age related alteration of the activity of metabolic
enzymes. As such the decreased activity of CYP3A4 and UGT1A
are good candidates for such an explanation. Increased bilirubin
levels were found to be related with a decreased clearance. Unfortunately no data on children below the age of 1 year were included.321 Bomgaars et al. studied PK in 79 pediatric patients
(median age 9 years, range 123 years). Although reported in
adults they did not nd a relation of UGT1A1 genotype versus neutropenia and gastro-intestinal toxicity. However in children a high
inter-patient variability in clearance, conversion and glucuronidation was reported.322 Vassal et al. studied 81children ranging from
0.9 to 18.5 years (median 8 years). They found no differences in

relation to PK in relation to age.323 Based on these reports no clear
statements can be made on very young infants. Based on the decreased activity of UGT1A1 in the very young children allometric
dosing might result in increased toxicity. From the age of 0.9 years
allometric dosing might result in lower levels of activity.
Anti-tumor antibiotics
Doxorubicin and daunorubin
The mode of action of all anthracyclines is in principle 4-fold:
activation of protein C-kinase-mediated signal transduction pathways, generation of oxygen intermediates, stimulation of apoptosis, and inhibition of DNA topoisomerase II catalytic activity. All
anthracyclines, as well as mitoxantrone, show prolonged tissue
binding.
After intravenous administration daunorubicin is bound for
about 60% to plasma proteins. Rapid distribution to the tissues,
especially liver, lungs, kidneys and heart occurs. There is no penetration in the central nervous system. The concentration in leukemia cells can be substantially higher. Up to 700 times higher
intracellular levels as compared to plasma levels were reported.
The drug is eliminated for 25% as active drug in a period of 5 days.
Excretion in the bile is more important than excretion in the urine
(only 25%). Distribution of doxorubicin is similar to daunorubicin,
except that the renal excretion is lower; i.e. 10%.
Doxorubicin: In plasma the parent drug predominates. The drug
is a substrate for CYP2D6 and CYP3A4.41 The most important
metabolite is doxorubicinol, which is only present in limited
amounts. About 50% of the drug, its metabolites, including aglycones, and the glucuronidated and sulphated forms are excreted
in the bile. There is extensive binding to DNA and proteins, leading
to a terminal t of 3050 h. Modeling experiments indicate that
there is an increased clearance at younger ages. Since the youngest
person was only 17, the applicability for the pediatric age range
can only be extrapolated.324 Others did not reveal shifts in Cmax
in relation with age.325,326
In children PK is highly variable. In the report of Frost et al. in
107 children from 1.3 to 17.3 years of age (median 4.7 years) highest median peak plasma concentrations were found in 46 year old
children (77 ng/ml). Children below the age of 2 years (n = 10) and
those >6 years had values below 50 ng/ml. Doxorubicinol/doxorubicin ratios varied from 0 to 0.81 (median 0.13).327 Another study
by a Swedish group was done in children with AML. Four children
below the age of 2 years had similar blood levels on lower dosages
as compared with the 33 children above that age, they needed
higher dosages to reach similar blood levels. No differences in
doxorubicinol/doxorubicin ratios were found. A separate group of
four Down syndrome patients showed 65% lower doxorubicin levels as compared with non-Down patients. However, this was due
to dose reductions. In these four children clearances were similar
to non-Down patients. Therefore they did not recommend dose
reductions for patients with Down syndrome. The authors further
demonstrated a clear correlation of plasma clearance and efcacy
of induction treatment for the whole group of patients in their
study.328 A decreased clearance of doxorubicinol has been demonstrated in children with a body fat percentage over 30%. The clearance of the parent drug was not inuenced by the composition of
the body. Infants experience cardiotoxicity after lower dosages.
Doxorubicinol might contribute to cardiotoxicity. Whether cardiotoxicity is related to fat percentage related volume of distribution
of doxorubicinol is hard to conclude since the authors only included children from 5.7 years onwards.329 In a study including 8
children below the age of 2 years signicantly lower clearances
were found as compared to 52 older children. Sorting out the 4
children below the age of 1 year (0.170.83 years) signicance was

lost, which was probably due to the small numbers.197
Daunorubicin: In contrast to doxorubicin, the parent compound
is rapidly cleared and daunorubicinol is the predominant active
compound in the plasma. Similar to doxorubicin there is extensive
binding to DNA and proteins. Metabolic pathways are similar to
doxorubicin. Clearance has been shown to be delayed in children
<10 years. In 8 children <2 years of age clearance was even slower.
However, statistical analysis did not reveal signicance for these
very young patients.197 Data on PK of daunorubicin in infants are
very scarce. The advise to consider full dosing from 3 to 6 months
should be taken with some caution considering the lower clearance below the age of 2 years.6 This is supported by the recent publication of Hempel et al. they investigated 21 patients with ALL
(age range 0.051.88 years; among them 5 infants <0.5 years and
15 ranging in age from 6 to 12 months) and the authors compared
the data with ndings in older children (age range 1.618.8 years).
Body surface area corrected pharmacokinetic data were not different between both groups. In the young children the daunorubicinol
levels were substantial lower due to the dose reductions that had
been applied in this age group. As a result age related dose reductions were not advised. What the effect of abstaining from dose
reductions will mean for side effects, such as cardiotoxicity, is
unclear.10
Liposomal constructs claim to be less cardiotoxic, but there are
no data in infants to conrm.
Epirubicin
Distribution of epirubicin is similar to doxorubicin. Elimination
is mainly in the bile; only a few percent of the drug is excreted in
urine. The mode of cytostatic activity is similar to doxorubicin and
daunorubicin. Metabolites formed in the liver are epirubicinol and
glucuronides of epirubicine and epirubicinol. Eksborg studied PK in
31 children including children <2 year. They found no correlation
of PK data with age.326
Idarubicin
After intravenous administration, there is, similar to other anthracyclines, substantial tissue penetration. As a result there is a high
volume of distribution and long terminal t. In leukemia patients
higher concentrations were found in the blood cells. Metabolic enzymes involved in the metabolic process are CYP2D6 and
CYP2C9.41 The primary metabolite, idarubicinol, is cytotoxic and
levels in the plasma are higher than the levels of the parent compound.330 Excretion is for 80% as 15-idarubicinol, and, the major
way of secretion is via the bile. The mode of cytostatic activity is
similar to other anthracyclines.
PK in a cohort with children P1 year of age were not inuenced
by the age as such.313 Another study providing details on PK measurements in patients >2 years did not reveal any age-related
changes in PK.331
17
metabolites have no anti-tumor activity. Oxidation by CYP-450 enzymes has been claimed.335 Breakdown of the product is by oxidation to mono-and dicarboxyl acids.336 Within 5 days 10% of the
drug and metabolites are excreted in the urine, 65% as parent drug
and the remaining 35% as metabolites. In the same 5 days about
20% can be recovered from the feces.337 No pharmacokinetic data
for infants are known.
Dactinomycin
Dactinomycin exerts it cytostatic activity by binding to DNA
and inhibition of RNA and protein synthesis. After intravenous
administration the drug accumulates in nucleated cells. Dactinomycin levels in the serum quickly decline as the drug binds to cells
and tissues, leading to a prolonged half-life >40 h in adults. No active metabolites were described. The drug is excreted through the
urine and in the bile. Within 1 week one third of the administered
drug is found unaltered in the urine and feces, i.e. 20% and 14%
respectively.
In a study on 33 patients (aged 1.620.3 years; mean 9.9) age
was analyzed as one of the covariates, but age was not found to
inuence PK.338 In a study in the United Kingdom 31 patients from
the age of 1 year onwards (median 7 years) children showed that
children below the age of 36 months suffered more often from
hepatotoxicity. There is an advice to decrease the dosage by in infants 50%.6 From the cited UK study, however, the number of PK
samples from patients under the age of 3 years was too low to
make adequate PK assessments.339 Based on the high tissue binding it is even doubtful whether PK data will be very informative
in relation to pharmacodynamic and toxicity data in infants. As a
result a careful reporting of efcacy and side effects seem to be
the most relevant points to assess dosing.
Bleomycin
Marketed bleomycin is a composite of multiple glycopeptides.
Bleomycin complexes with several endogenous and exogenous
metals and is activated after microsomal reduction. The drug exerts its action through cleavage of the DNA.340 The drug is metabolized by hydrolysis, taking place in several tissues. Lung toxicity is
related with local hydrolysis of the drug in the lung. Bleomycin is
only given in a few types of malignancies. After parenteral administration distribution of bleomycin to lungs, liver, kidney is very rapid. Forty to 70% is excreted in the urine 24 h.341,342 Excretion is
strongly linked to creatinin clearance.
PK data are scarce. In a study on 14 children PK were found to
be similar to adults. Children with an impaired renal function
had a more prolonged exposure to the drug. In the 3 children below the age of 3 years elimination half-lives were a bit shorter then
in older children, whereas total plasma clearances were signicantly higher (70 versus 45 m/min/m2) in older children.343 For infants no recommendations can be made.
Mitoxantrone
Miscellaneous drugs
Mitoxantrone is an anthracenedione which is closely related to

commonly used anthracyclines. It binds to nucleic acids and inhibits DNA and RNA synthesis. Mitoxantrone intercalation of DNA has
a preference for GC base pairs,332 but also stochastic hindrance
resulting in compaction of chromatin results in anti-tumor activity.333 The free-radical mechanism is less than in anthracyclines,
which results in substantially less cardiotoxicity.334 Characteristics
of mitoxantrone have high similarity as compared to anthracyclines. Similar to the doxorubicin and daunorubicin there is a high
tissue binding, resulting in terminal t of over 60 h. The known
Cisplatin
Cisplatin and its analogs exert their action by covalent binding
to purine-DNA bases, resulting in interference with normal function of DNA. After administration in 2 h infusions 90% of the drug
is protein bound. There is high penetration to tissues such as liver,
kidneys, testicles, colon and small bowel. There is no penetration in
the central nervous system. There is prolonged binding of cisplatin
in the body. Even after decades platinum can be detected in treated
individuals.344 Enzymes involved in the metabolic process are
18
CYP2E1 and 3A4.41 An important route of renal elimination of cisplatin is conjugation with glutathion adducts.345 Elimination is for
90% renally in a combination of glomerular ltration and tubular
secretion. Ten percent is eliminated by biliary excretion. Terminal
t is several days (up to 240 h are reported). The high variability in
PK has been related to this binding.346,347 The variability has resulted in a recommendation in adults not to dose on basis of
BSA, but instead to use xed dosages.348 The amount of adducts
of cisplatin with DNA are related with efcacy and toxicity.
However, in children no relation of adducts versus PK parameters
of unbound or total cisplatin levels was found.349 Bues-Charbit et al.
studied 4 children (16 months, 18 months, 6 years and 12 years).
Median t was 81 h, 35% of the ultralterable platinum was recovered from the urine within 48 h, although after 10 days the drug was
still detectable.350 In a study on 21 children, including two children
below the age of 2 years quite different parameter came up with for
instance a t of 40 min. This might indicate that in older children the
clearance is substantially higher as compared to infants. As a result
the body surface area based dosing was severely questioned. Later
an advice was formulated to categorize patient according to body
surface area in one of the three groups (61.65 m2; 1.662.04 m2;
P2.05 m2).351,352 A weight, t and Cmax based equitation has been
constructed covering the PK prole in a better way.353 Unfortunately
no data on infants were obtained and dose recommendations are
hard to give due to above mentioned factors.
Carboplatin
Mode of action is comparable to cisplatin. Major advantage is
the reduced non-hematologic toxicity as compared to cisplatin.
The formation of DNA adducts is lower. There is a linear relation

between dosage and total amount of platinum in the plasma. It
takes more than 24 h to reach half of the peak level. Over 65% of
carboplatin is excreted in the urine. Total body clearance correlates
with glomerular ltration, but not with tubular excretion.
In 28 children (including 4 children <5 years) the quantity of adducts could be correlated with AUC data. As a result PK data are
more informative than in cisplatin. In 19 patients below the age
or 15 months with body weights below 12 kg with neuroblastoma
treated with carboplatin in combination with etoposide; carboplatin clearance values ranged from 12.8 to 33.6 ml/min, with total
AUC values of 4.29.3 mg/ml.min achieved over the 3 days of treatment. Comparison with historical data from children with a body
weight above 12 kg clearances were signicantly higher in the
smaller children.287 In a study starting with administration of standard dosages, dose adjustments had to be made in 75% of the children on basis of the observed AUC. The measured AUCs were
correlated with glomerular ltration rates.349,354 In a study in 57
children (median age 5 years; range 2 months to 18 years) a complex equation was computed including weight and serum creatinin
in order to predict the clearance rate of carboplatin. Applying this
equation resulted in a signicantly decreased alteration of dosing
decreased from 74% to 29%.355 Also a simpler equation was constructed from data of 22 patients (including 4 infants <1 year and
3 below the age of 2 years) based on GFR and to a lesser extent
on body weight.356 In the report of Picton et al. a preterm neonate
with bilateral retinoblastoma was treated under drug monitoring.
After increasing the dosages they observed that the AUC was not
correlated with the dosage given. Doubling the dosage resulted
in more than twice an increment of the AUC.357 Tonda et al.
Table 2
Major identied ontogenic factors on drug metabolizing enzymes in infants.
Drug
Fetal expression, silenced or low expression

within 12 years a
Fetal expression at relatively constant level; some

postnatal increasea
Activation
Activation
Degradation
Activation
Degradation
CYP2C9
CYP2C19
CYP3A5
GSTA1
CYP2B6
CYP3A4
CYP3A4
ADH
ALDH
GST
Ifosfamide
CYP2B6
CYP3A4
CYP3A4
ALDH
ADH
GST
Procarbazine
CYP2B6
CYP1A
Dacarbazine
CYP1A1
CYP1A2
CYP2E1
Cyclophosphamide
Degradation
Substantial increase in the rst

12 yearsa
Temozolamide
Thiotepa
Busulfan
CYP3A4
CYP2B6
GST
CYP3A4
Paclitaxel
CYP2C8
CYP3A4
Docetaxel
CYP3A5
Etoposide
CYP3A5
Topotecan
Doxorubicin /Daunorubicin
Mitoxantrone
According to Hines 2008 and Mc Carver 2002.
CYP3A4
CYP3A4
CYP1A1/2
CYP3A4
Irinotecan
CYP3A4
Vinca alkaloids
CYP3A4
CYP2D6
CYP3A4
CYP3A
19
described in less than 1 years of age, that carboplatin clearance per

square meter is approximately 40% lower than seen in patients
14 years of age.358
Oxaliplatin
Also oxaliplatin has many similarities with the other platin compounds (e.g. mode of action and renal excretion).359 After administration the drug accumulates in red blood cells and in plasma. The
metabolism is not fully characterized, but the excretion is expected
to be mainly renal. Oxaliplatin administration gives less formation
of DNA-adducts. Further differences are presumed to be related to
the different effect on DNA polymerase(s), mismatched repair activity, and Pt-DNA damage recognition proteins.360 In a pediatric study
in 43 children (median age 8.5 years; range, 0.618.9 years) similar
PK data were found as in adults.361
Formulation
It is generally assumed that children below the age of 6 years
experience problems with the swallowing of tablets and capsules.
Due to local mucosal toxicity or due to the absence of gastro-intestinal uptake or limited or erratic gastro-intestinal absorption only a
limited number of cytostatic drugs can be administered orally (often on maintenance basis). The formulation issue can form a tremendous hurdle and use of extemporaneous formulations are
common practice. Data on bioavailability using these formulations
are lacking and adequate dosing is merely based on assumptions.
There are only tablets or capsules but no approved liquid formula-
tions available for those drugs that can in principle be administered orally; i.e. cyclophosphamide, procarbazine, temozolamide,
lomustine, chlorambucil, busulfan, melphalan, methotrexate,
6-mercaptopurine, 6-thioguanine, udarabine, vinorelbine, etoposide, topotecan, The lack of an appropriate formulation for temozolamide, methotrexate, 6-mercaptopurine and 6-thioguanine is felt
as the most annoying lack in the provision of medication to
children.
Conclusion
As indicated earlier, dosing in infants dose recommendations is
often based on extrapolation from data in older children, which is
in most cases is not based on scientic data. Most treatment protocols merely advise either standard dose reductions for all cytostatic
drugs or they advise in children below a certain age the use of
other parameters (e.g. weight instead of body surface area). The
current methods to predict PK and adequate dosing; i.e. modeling/pharmacometrics, give acceptable results for older children.
However below the age of 3 years the result do need substantial
improvement.362,363 In this review data on both ontogeny of metabolic pathways and data from PK studies in infants were collected
from literature. Major points that become evident were the shifts
in activity of metabolic pathways related to ontogeny. Especially
the phase I and II enzymes are known for the volatile changes in
activity. Renal elimination pathways probably show a more gradual development. In respect to the metabolism of cytostatic drugs
two aspects merit special attention. Firstly, generally we do not
know if enzymes, which are characteristic for infants and do not
Table 3
Summary of differences in ADME in infants compared to adults.
Drug
Cyclophosphamide
Ifosfamide
Procarbazine
Dacarbazine
Temozolamide
Thiotepa
Lomustine/Carmustine
Chlorambucil
Busulfan
Melphalan
Ara-C
Gemcitabine
Methotrexate (oral)
Methotrexate (intravenous)
Pemetrexed
6-mercaptopurin
6-thioguanin
5-uorouracil
Fludarabine
Cladribine
Vinca alkaloids
Taxanes
Etoposide
Teniposide
Irinotecan
Doxorubicin/Daunorubicin
Epirubicin
Mitoxantrone
Dactinomycin
Bleomycin
Cisplatin
Carboplatin
Oxaliplatin
Absorption
NR
NR
ND
ND
ND (decreased ??)
NR
ND
ND
ND
NR
NR
NR
ND
NR
NR
ND
ND
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
Metabolism
Elimination
Activation
Decay
Renal
Biliary
Decreased
Decreased
Decreased
Decreased
Normal
Decreased
Decreased
ND
Intracellular tumor cell dependent
Decreased
Decreased
ND
ND
Decreased
Decreased
Decreased
Decreased
ND
ND
ND
+
+
+
+
+
+
+
+
+
+
+
+
+
+

ND
ND
ND
Decreased
Decreased
Decreased
Decreased ?
TPMT dependent
TPMT
ND
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
ND
Decreased
Decreased
?
+

+
+

+
+
+
+
+
+

+
+
+
+
+
+
+
+
+

NR, not relevant due to intravenous administration; , not applicable; ND, no data.
20
come to expression at later ages, are involved in the metabolism of

cytostatic drugs. As a result we might be unaware of substantial
amounts of either active or inactive metabolites of the parent drug,
resulting in either increased or decreased activity and unexpected
toxicity. Secondly, a high percentage of administered cytostatic
drugs are prodrugs with no or limited cytostatic activity. Decreased
activation might, in case the parent drug is not excreted, lead to a
prolonged period of exposure to the active drug. The concentration
of active compounds is dependent on the activity of the, often
immature, elimination mechanisms of these metabolites. In case
the parent drug has a delayed activation and the parent compound
is excreted in a normal or higher amount, less active drug will be
present. Both phenomena inuence pharmacodynamics. For cytostatic drugs not in need for activation the differences in metabolic
pathways and elimination routes will lead to other (often increased) toxicity (see Table 1). A summary of the literature data
on the various enzymes can be found in Table 2. Making assumptions from these data is still difcult; since no data on the use of
alternative pathways and alterations in expression and activity of
isoforms of the specic enzymes on cytostatic drugs related to infancy are known. For several drugs the consequences of differences
in tissue binding, volume of distribution related to another composition of the body and alternative cell entry characteristics in infancy are unknown. For drugs like dactinomycin and bleomycin
this might be quite important. Another issue of importance are
the differences in handling of cytostatic drugs in various malignancies. Striking differences in metabolic handling can occur as compared to adult forms of the same malignancy. But in the same
disease within the pediatric age group differences exist in relation
to subtyping based on immunology, cytogenetics and even age.
From the heterogeneous data from the various drugs only limited
general recommendations can be formulated. In principle for those
drugs that might have a lower rate of activation and/or a decay a
prolonged exposure is likely. In relation to this phenomenon prolonged intervals between the cytostatic courses could be considered to optimize recovery from hematological and nonhematological side effects of the drug. For drugs were the elimination (both renal and biliary) might be prolonged, decreasing the
dosages seems to be logical in order to prevent too high peak values. In case of renal elimination, dose adaptations can be considered using data on actual renal function. Based on these data
drugs for which prolongation of interval and a lower dosage should
be considered are: cyclophosphamide, ifosfamide, procarbazine,
dacarbazine, temozolamide, lomustine, carmustine, vinca alkaloids, taxanes, all topoisomerase inhibitors, all anthracyclines,
mitoxantrone, all platinum-based drugs and bleomycin. At least
dose reductions should be considered for melphalan, Ara-C, gemcitabine, methotrexate, pemetrexed, 6-mercaptopurin, 6-thioguanin, 5-uorouracil, udarabine, cladribine and dactinomycin (see
Table 3). For oral busulfan there are adequate recommendations,
although due to the high variance dose monitoring and use of
the intravenous formulation is preferred. In respect to the age
groups within the infant group, the above made recommendations
are valid for ages up to the 6 months after birth. Later on there will
be shifts to PK as seen in older children. However, it is likely that
for each cytostatic drug the moment and the speed these shift occur will be different.
The summarized data as collected from the literature clearly
illustrate that the administration of cytostatic drugs in infants is
currently often not based on PK data. As such the statement that
each infant treated with cytostatic medication is eligible for pharmacokinetic determinations is valid. As a consequence researchers
should publish their results. Compiling these data in a global database would enable evidence-based drug therapy in infants with
malignancies, resulting in a more effective treatment and less toxic
treatment in this vulnerable population.
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Chemo in Children

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Cancer Treatment Reviews 38 (2012) 326

Contents lists available at ScienceDirect

Cancer Treatment Reviews

Cytostatic drugs in infants: A review on pharmacokinetic data in infants

ious drugs (pharmacodynamics) may be different in children with

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

the metabolic capacity is completely neglected this way.7 Even in a

soluble drugs have relatively larger distribution volumes in infants

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

Duration of exposure prolonged

Duration of exposure prolonged

Duration of exposure prolonged

Duration of exposure prolonged

Duration of exposure normal

Duration of exposure decreased

individuals considerable differences in metabolic capacity. These

variants are devoid of any activity.45 CYP2A6 is found in adult liver

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

Flavin-containing monooxygenase system (FMO). In man only FMO1,

Alcohol dehydrogenase. Alcohol dehydrogenase is encoded by seven

Aldehyde dehydrogenase. Aldehyde dehydrogenase enzymes are a

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

increase in UGT2B7 activity across ve age groups,<1 year of age,

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

toxicity related to the dechloromethyl-metabolite.115117 CYP 3A4

absorption with a higher dosage.128 With low doses (12 mg/kg)

Fig. 1. Metabolism of cyclophosphamide. The enzymes with highest activity are

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

months of life substantial reductions are necessary. In addition

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

ous decomposition is pH dependent. Increased turnover is noted at

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

Lomustine (CCNU) and carmustine (BCNU)

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

age. The total dosage needed to achieve comparable blood levels

concentrations were found to be several hundred-fold higher than

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

clearance is suspected, but in multivariate analysis this seemed not

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

0.9 to 18.5 years (median 8 years). They found no differences in

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

children below the age of 1 year (0.170.83 years) signicance was

Mitoxantrone is an anthracenedione which is closely related to

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

The formation of DNA adducts is lower. There is a linear relation

Fetal expression, silenced or low expression

Fetal expression at relatively constant level; some

Substantial increase in the rst

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

described in less than 1 years of age, that carboplatin clearance per

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

come to expression at later ages, are involved in the metabolism of

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

60. Andrew M, Marzinotto V, Brooker LA, Adams M, Ginsberg J, Freedom R, et al.

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

88. Alnouti Y, Klaassen CD. Tissue distribution, ontogeny, and regulation of

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

175. Bostrom B, Enockson K, Johnson A, Bruns A, Blazar B. Plasma pharmacokinetics

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

227. Lennard L, Welch J, Lilleyman JS. Intracellular metabolites of mercaptopurine

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326

H. van den Berg et al. / Cancer Treatment Reviews 38 (2012) 326