Pharmacokinetics: A Refresher

PHARMACOKINETICS:
A REFRESHER
CURTIS L. SMITH, PHARM.D. BCPS
FERRIS STATE UNIVERSITY
LANSING, MICHIGAN

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 Pharmacokinetics: A Refresher
Learning Objectives:
1. Identify and provide examples using basic pharma-
cokinetic concepts commonly used in clinical prac-
tice, including elimination rate constant, volume of
distribution (V d), clearance, and bioavailability.
2. Describe specific pharmacokinetic characteristics
of commonly used therapeutic agents.
3. Define important issues as they relate to drug con-
centration sampling and interpretation.
Self-Assessment Questions:
Answers to these questions may be found at the
end of this chapter.
1. J.H., a 65-year-old woman (65 kg), was recently
initiated on tobramycin and piperacillin -tazobac-
tam for treatment of hospital-acquired pneumonia.
After the first dose of tobramycin 120 mg (infused
from noon to 1:00 pm), serum tobramycin concen-
trations are drawn. They are 4.4 mg/L at 3:00 pm
and 1.2 mg/L at 7:00 pm. Which one of the follow-
ing statements is true about tobramycin?
A. There are sufficient data to determine the
half-life (t 1/2) but not the V d.
B. There are sufficient data to determine both
the t 1/2 and Vd
C. There are insufficient data to determine either
the t1/2 or the Vd
D. There are sufficient data to determine the Vd
but not the t1/2.
2. P.L. is a 60-year-old woman (60 kg) recently ini-
tiated on gentamicin and clindamycin. After the
first gentamicin dose of 110 mg (infused from 6:00
pm to 6:30 pm), serum gentamicin concentrations
are drawn. They are 3.6 mg/L at 7:30 pm and 0.9
mg/L at 11:30 pm. Which one of the following best
describes this patient's gentamicin pharmacoki-
netic parameters?
A. The t]/2 is about 2 hours.
B. The t]/2 is about 3 hours.
C. The maximum concentration (Cmax) is about
3.8 mg/L.
D. The Vd is about 11.6 L.
3. R.O. is a 74-year-old woman initiated on genta-
micin 100 mg intravenously every 24 hours for
pyelonephritis. On admission, her serum creati-
nine (SCr) is 1.8 mg/dL. She also has congestive
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heart failure and is fluid overloaded because of her
diminished renal function and nonadherence to
her angiotensin-converting enzyme inhibitor and
diuretic. A few days into her hospitalization, her
SCr is down to 1.1 mg/dL, and she is reinitiated on
furosemide and enalapril. Which of the following
most likely happened to the gentamicin t1/2 in R.O.
during her hospitalization?
A. Her clearance increased, which increased her Vd
and decreased her t1/2
B. Her clearance increased, which increased her
elimination rate constant and decreased her t1/2.
C. Her Vd decreased, which increased her
clearance and decreased her t1/2.
D. Her Vd decreased, which increased her
elimination rate constant and increased her t1/2
4. A patient receives vancomycin 1000 mg intrave-
nously every 24 hours and has a trough concentra-
tion, drawn 30 minutes before the next dose, of 6
mg/L. Which one of the following regimens is best
for this patient if the goal trough concentration is
10-15 mg/L?
A. Maintain the dose at 1000 mg intravenously
every 24 hours.
B. Lower the dose to 500 mg, but keep the
interval at every 24 hours.
C. Keep the dose at 1000 mg, but shorten the
interval to every 12 hours.
D. Lower the dose to 500 mg, and shorten the
interval to every 12 hours.
5. A 40-year-old, 60-kg woman who smokes presents
to the emergency department at 2:00 pm with an
acute exacerbation of asthma. She takes theophyl-
line sustained release 300 mg 2 times/day, with the
last dose taken at 9:00 that morning. Her theoph-
ylline concentration soon after presenting to the
emergency department is 7.0 mg/L. She is stabi-
lized and is to be sent home on theophylline sus-
tained release. Which one of the following options
is the best regimen for this patient?
A. Theophylline sustained release 300 mg by
mouth every 12 hours.
B. Theophylline sustained release 600 mg by
mouth every 12 hours.
C. Theophylline sustained release 400 mg by
mouth every 8 hours.
D. Theophylline sustained release 600 mg by
mouth every 8 hours.
6. L.R. is a 49-year-old patient with diabetes mellitus
and renal failure. He was recently in a car accident
and sustained head trauma. He currently receives
 Pharmacokinetics: A Refresher

phenytoin 100 mg intravenously 3 times/day, and 9. A research group is analyzing the relationship be-
his most recent concentration was 5.6 mcg/mL. tween various independent patient demographics
You are asked to suggest a new dose to achieve a (e.g., age, height, weight, Alb, creatinine clearance
concentration within the therapeutic range. Labo- [CrCl]) and phenytoin pharmacokinetics. Which
ratory results include sodium 145 mEq/L, potas- one of the following statistical tests will need to be
sium 3.9 mEq/L, chloride 101 mEq/L, carbon di- used to assess the relationship?
oxide 26 mEq/L, blood urea nitrogen (BUN) 95 A. One-way analysis of variance.
mg/dL, SCr 5.4 mg/dL, glucose 230 mg/dL, and B. Analysis of covariance.
albumin (Alb) 2.8 g/dL. Which one of the follow- C. Multiple logistic regression.
ing choices is the best recommendation? D. Spearman rank correlation.
A. Increase the dose to 200 mg intravenously 3
times/day. 10. N.T. is a 24-year-old woman receiving valproic
B. Increase the dose to 200 mg intravenously 2 acid for tonic-clonic seizures. Her most recent
times/day. trough valproic acid concentration was 22 mg/L.
C. Decrease the dose to 100 mg intravenously 2 Her most recent Alb concentration was 4.1 g/dL.
times/day. Based on this serum concentration, which one of
D. Keep the dose the same. the following recommendations is best concerning
her dose?
7. You are asked how the TDx (fluorescence polar- A. Continue with the current dose; the
ization immunoassay) and EMIT (enzyme mul- concentration is close enough to the
tiplied immunoassay technique) assays compare therapeutic range.
with each other. Which one of the following state- B. Assess adherence and increase her dose; the
ments is most accurate? concentration is below the therapeutic range.
A. Although both are immunoassays, one labels C. Decrease her dose; the concentration is
antibody, whereas the other labels antigen. slightly above the therapeutic range.
B. Although both are immunoassays, one uses D. Assess adherence and then check a free
antibody as a marker, whereas the other uses valproic acid concentration and adjust
a radioisotope. accordingly.
C. Although both are immunoassays, one uses
an enzyme label, whereas the other uses a
fluorescent label.
D. They are both names for the same assay
technique.
8. An elderly patient is seen in the morning medicine
clinic for a routine follow-up. Medication history
includes digoxin 0.25 mg/day by mouth, furose-
mide 40 mg/day by mouth, and potassium chloride
10 mEq/day by mouth. All doses were last taken
at 8:00 am today at home. The patient has vague
complaints of stomach upset, which began 2 days
ago, but is otherwise in no apparent distress. A se-
rum digoxin concentration drawn today at 10:00
am is 2.5 mcg/L. Which one of the following state-
ments best describes what should be done next?
A. Admit the patient for administration of
digoxin Fab.
B. Tell the patient to skip tomorrow's dose of
digoxin and begin 0.125 mg/day by mouth.
C. Administer a dose of activated charcoal.
D. Do nothing today about the digoxin.

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 Pharmacokinetics: A Refresher

Patient Cases
1. H.R. is receiving vancomycin for a methicillin-resistant Staphylococcus aureus bacteremia. H.R. has chronic
renal failure. A 1-g intravenous dose of vancomycin is given at noon on March 21. A concentration drawn
at 2:00 pm on March 21 is 23.8 mcg/mL. A concentration drawn at 2:00 pm on March 24 is 12.1 mcg/mL. If
you were to give a dose at 4:00 pm on March 24 and your goal trough concentration was 10-15 mg/L, when
would it be best to give the next dose?
A. 1 day after the dose on the 24th.
B. 3 days from the dose on the 24th.
C. 6 days from the dose on the 24th.
D. There is not enough information to calculate when to redose.
2. After the administration of 100 mg of a drug intravenously and 200 mg of the same drug by mouth, the areas
under the curves are 50 and 25 mg/L/hour. Which one of the following is the bioavailability of this drug?
A. 25%.
B. 37.5%.
C. 50%.
D. 100%.
3. An infusion of 20 mg/hour of theophylline is initiated. Which one of the following best represents what the
serum concentration would be at 48 hours if the t1/2 of the drug were 4 hours and the V d were 0.5 L/kg (your
patient weighs 65 kg)?
A. 3.6 mg/L.
B. 5.0 mg/L.
C. 18.2 mg/L.
D. 30.4 mg/L.

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 Pharmacokinetics: A Refresher

II. ABSORPTION
A. First-pass Effect
1. Blood perfusing virtually all the gastrointestinal tissues passes through the liver by means of
the hepatic portal vein.
a. Fifty percent of the rectal blood supply bypasses the liver (middle and inferior
hemorrhoidal veins).
b. Drugs absorbed in the buccal cavity bypass the liver.
2. Drugs affected most by the first-pass effect are those with a high hepatic extraction ratio.
3. Example
Amitriptyline Labetalol Nitroglycerin
Desipramine Lidocaine Pentazocine
Diltiazem Metoprolol Propoxyphene
Doxepin Morphine Propranolol
Imipramine Nicardipine Verapamil
Isosorbide dinitrate Nifedipine

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 Pharmacokinetics: A Refresher

B. Enterohepatic Recirculation
1. Drugs are excreted by the bile into the duodenum, metabolized by the normal flora in the
gastrointestinal tract, and reabsorbed into the portal circulation.
2. Occurs in drugs with 1) biliary (hepatic) elimination and 2) good oral absorption
3. Drug is concentrated in the gallbladder and expelled on sight, smell, or ingestion of food.
Examples of Compounds Excreted in Bile and
Subject to Enterohepatic Cycling
Compound Entity in Bile
Chloramphenicol Glucuronide conjugate
Digoxin Parent
Estrogens Parent
Imipramine Parent and desmethyl metabolite
Indomethacin Parent and glucuronide
Nafcillin Parent
Rifampin Parent
Sulindac Glucuronides of parent and metabolites
Testosterone Conjugates
Tiagabine Glucuronide conjugate
Valproic acid Glucuronide conjugates
Vitamin A Conjugates

Patient Case
4. Which one of the following statements best describes P-glycoprotein?
A. It is a plasma protein that binds basic drugs.
B. It transfers drugs through the gastrointestinal mucosa, increasing absorption.
C. It diminishes the effect of cytochrome P450 3A4 (CYP3A4) in the gastrointestinal mucosa.
D. It is an efflux pump that decreases gastrointestinal mucosal transport.

1. P-glycoprotein is an efflux pump (located in the esophagus, stomach, and small and large
intestines) that pumps drugs back into the gastrointestinal lumen; it is a more important fact or
in drug absorption drug interactions than intestinal CYP3A4.
2. CYP3A4 and P-glycoprotein located in small intestinal enterocytes work together to decrease
the absorption of xenobiotics.
3. Most CYP3A4 substrates are also P-glycoprotein substrates.
4. Many CYP3A4 inhibitors/inducers also inhibit/induce P-glycoprotein, leading to increases or
decreases in bioavailability.
5. Examples of P-glycoprotein absorption drug interactions include quinidine or verapamil and
digoxin; rifampin or St. John's wort; and human immunodeficiency virus protease inhibitors.

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 Pharmacokinetics: A Refresher

III. DISTRIBUTION
A. Definition: Apparent V d —proportionality constant that relates the amount of drug in the body to an ob-
served concentration of drug
B Protein Binding
. Protein Types of Drugs Bound Molecular Weight Normal Concentrations
(g/L) (µmol)
Albumin Acidic 65,000 35-50 500-700
α -1-acid glycoprotein Basic 44,000 0.4-1.0 9-23
Lipoprotein Lipophilic and basic 200,000-3,400,000 Variable Variable
C. P-glycoprotein
1. P-glycoprotein is an efflux pump that mediates blood-brain barrier transport by limiting
uptake into or increasing the efflux out of brain epithelial cells.
2. It may be especially important with opioids—induction of P-glycoprotein by chronic use of
opioids decreases the opioid effect (tolerance).
3. P-glycoprotein is also found in tumor cells, resulting in the efflux of chemotherapeutic agents
out of the cell and, ultimately, multidrug resistance.

IV. CLEARANCE
Enzymes Involved in Drug Metabolism
Oxygenases Hydrolytic Enzymes
CYP450s Esterases
Monoamine oxygenases Amidases
Alcohol dehydrogenases Epoxide hydrolases
Aldehyde dehydrogenases Dipeptidases
Xanthine dehydrogenases
Conjugating Enzymes
Uridine diphosphate—glucuronyl transferases
Glutathione S-transferase
Acetyltransferases
Methyltransferases
CYP = cytochrome P450.

Patient Case
5. A renal transplant patient receiving cyclosporine receives a diagnosis of community-acquired pneumonia.
The patient is admitted to the hospital and initiated on ceftriaxone and a macrolide. Which one of the
following macrolides is least likely to interact with cyclosporine?
A. Erythromycin.
B. Clarithromycin.
C. Azithromycin.
D. All the macrolides inhibit CYP3A4.

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 Pharmacokinetics: A Refresher

1. Introduction
a. A group of heme-containing enzymes responsible for phase 1 metabolic reactions
b. Characteristic absorbance of light at 450 nm (thus CYP450)
c. Primarily located in the membranes of the smooth endoplasmic reticulum in 1) liver, 2)
small intestine, and 3) brain, lung, and kidney
d. Encoded by a supergene family or subfamily; separate genes code for different
isoenzymes
e. Drugs will generally have a high affinity for one particular CYP450, but most drugs also
have secondary pathways.
f. Nomenclature

CYP 3 A 4
Specific enzyme

Subfamily (> 70% identical)

Family (> 40% identical)
GENE for mammalian cytochrome
Figure 1.

2. Distribution of CYP450 isoenzymes in human liver

Content Role in CYP-mediated Drug Elimination

Figure 2.

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 Pharmacokinetics: A Refresher

3. Distribution of CYP450 isoenzymes in human gastrointestinal tract

other CY
30%

CYP3A4
70%

Figure 3.
4. Characteristics of CYP450 metabolism
a. Inhibition is substrate-independent.
b. Some substrates are metabolized by more than one CYP450 (e.g., TCAs [tricyclic
antidepressants], SSRIs [selective serotonin reuptake inhibitors]).
c. Enantiomers may be metabolized by a different CYP450 (e.g., warfarin).
d. Differences in inhibition may exist within the same class of agents (e.g., fluoroquinolones,
azole antifungals, macrolides, calcium channel blockers, H 2 blockers).
e. Substrates can also be inhibitors (e.g., erythromycin, verapamil, diltiazem).
f. Most inducers and some inhibitors can affect more than one isozyme (e.g., cimetidine,
ritonavir, fluoxetine, erythromycin).
g. Inhibitors may affect different isozymes at different doses (e.g., fluconazole).
B. P-glycoprotein
1. P-glycoprotein is an efflux pump that pumps drugs into the bile; the clinical effect of
P-glycoprotein drug interactions in the bile is unknown.
2. P-glycoprotein pumps drugs from renal tubules into the urine; it also potentially limits the degree
of reabsorption.
3. Examples of drug interactions: quinidine-digoxin, cyclosporine-digoxin, and propafenone-digoxin
C. Pharmacogenetics/Polymorphic Drug Metabolism
1. Population is divided into poor metabolizers and extensive metabolizers; therefore, metabolism is
considered polymorphic.
2. Definition: coexistence of more than one genetic variant (alleles), which are stable components in
the population (more than 1% of population)
3. Clear antimode results

No. of Patients

Metabolic Ratio (increasing metabolic capacity ---------

EM = extensive metabolizer; PM = poor metabolizer; URM = ultrarapid extensive metabolizer.
Figure 4.

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 Pharmacokinetics: A Refresher

4. Phenotype: expression of the trait

a. Manifestation of the trait clinically
b. Not necessarily constant
5. Genotype: genetic makeup
a. Constant: can be tested
Table 1.
Pathway Substrate Enzyme Drug Examples
Oxidation Debrisoquine, dextromethorphan CYP2D6 Tertiary amines
Fluoxetine
Flecainide
Propafenone
Metoprolol
Propranolol
Timolol
Codeine
Oxidation Mephenytoin CYP2C19 Tertiary amines (diazepam)
Phenytoin
Omeprazole
Acetylation Isoniazid, caffeine N-acetyl transferase Clonazepam
Dapsone
Hydralazine
Inamrinone
Procainamide
Sulfonamides

V. NONLINEAR PHARMACOKINETICS

Patient Case
6. C.M. is a 55-year-old man who is initiated on phenytoin after a craniotomy. His current steady-state phenytoin
concentration is 6 mg/L at a dose of 200 mg/day by mouth. If his affinity constant (K m) is calculated to be 5
mg/L, what will happen to his concentration if the dose is doubled (to 400 mg/day by mouth)?
A. His concentration will double because phenytoin clearance is linear above the Km.
B. His concentration will more than double because phenytoin clearance is nonlinear above the K m.
C. His concentration will stay the same because phenytoin is an autoinducer, and clearance increases with time.
D. His concentration will increase by only 50% because phenytoin absorption decreases significantly with
doses greater than 300 mg.

A. Michaelis-Menten Pharmacokinetics
Velocity = Vmax * SKm + S
Vmax = capacity constant (amount/time)
Km = affinity constant (amount/volume)
S = substrateconcentration (amount/volume)

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 Pharmacokinetics: A Refresher

B. Nonlinear Elimination
1. Saturation or partial saturation of the elimination pathway
Rate of elimination = Vmax * CKm + C
Vmax = maximum rate of elimination (amount/time)
Km = concentration where elimination is 1/2 Vmax (affinity constant)
C = drug concentration
2. Note: Nonlinearity occurs when concentration is at or above K m
a. Example: phenytoin
i. Vmax normal = 7 mg/kg/day
ii. Km normal = 5.6 mg/L
iii. 50% variability between individuals
VI. NONCOMPARTMENTAL PHARMACOKINETICS
A. Why Noncompartmental Pharmacokinetics?
1. Identification of the "correct" model is often impossible.
2. A compartmental view of the body is unrealistic.
3. Linear regression is unnecessary—it is easier to automate analysis.
4. Requires fewer and less stringent assumptions
5. More general methods and equations
6. There is no need to match all data sets to the same compartmental model.

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 Pharmacokinetics: A Refresher

2. Volume of distribution at steady state

VSS = dose * AUMC
AUC2
3. Elimination rate constant
k = 1MRT
4. Absorption rate constant
Ka = 1MAT

5. Bioavailability
F = Div * AUCevDev * AUCiv

VII. DATA COLLECTION AND ANALYSIS

Patient Case
7. R.K. is a 54-year-old woman with a history of diabetes mellitus and end-stage renal disease. She is receiving
gentamicin for Pseudomonas pneumonia. A gentamicin concentration is ordered after dialysis. Which one
of the following statements is true about obtaining this sample?
A. The most accurate concentration is obtained immediately after hemodialysis.
B. Wait a few hours to obtain the concentration because it will decrease
significantly within the first few hours after hemodialysis.
C. Wait a few hours to obtain the concentration because it will increase
significantly within the first few hours after hemodialysis.
D. Wait until the next day so that all the effects of hemodialysis have abated.

A. Timing of Collection
1. Ensure completion of absorption and distribution phases (especially digoxin and
vancomycin, etc.).
2. Ensure completion of redistribution postdialysis (especially aminoglycosides).

B. Specimen Requirements
1. Whole blood: Use anticoagulated tube.
2. Plasma: Use anticoagulated tube and centrifuge; clotting proteins and some blood cells are
maintained.
3. Serum: Use red top, allow to clot, and centrifuge.

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Patient Case
8. A drug assay is touted as having high specificity but low sensitivity. Which one of the following statements
best describes what this means?
A. The assay will not be able to distinguish the drug from like products,
but it will be able to detect extremely low concentrations.
B. The assay will not be able to distinguish the drug from like products, and
it will not be able to detect extremely low concentrations.
C. The assay will be able to distinguish the drug from like products and
will be able to detect extremely low concentrations.
D. The assay will be able to distinguish the drug from like products but
will not be able to detect extremely low concentrations.

C. Sample Analysis
1. Assay terminology
a. Precision (reproducibility): closeness of agreement among the results of repeated
analyses performed on the same sample
i. Standard deviation (SD): average difference of the individual values from the mean
ii. Coefficient of variation (CV): SD as a percentage of the mean (relative rather than
absolute variation)

b. Accuracy: closeness with which a measurement reflects the true value of an object
i. Correlation coefficient—strength of the relationship between two variables
c. Predictive performance (accuracy)
Precision: a.k.a. root mean square error (RMSE)

Bias: a.k.a. mean prediction error (ME)

**Prediction error (pe) is the prediction minus the true value.

d. Sensitivity: ability of an assay to quantitate low drug concentrations accurately; usually
the lowest concentration an assay can differentiate from zero
e. Specificity (cross-reactivity): ability of an assay to differentiate the drug in question from
like substances

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 Pharmacokinetics: A Refresher

D. Assay Methodology
1. Immunoassays
a. Radioimmunoassay
i. Advantages: extremely sensitive (picogram range)
ii. Disadvantages: Radioimmunoassay kits have limited shelf life because of the short
t]/2 of labels, nuclear waste, and cross-reactivity.
**Clinical use for assaying digoxin and cyclosporine
b. Enzyme immunoassay
ex. EMIT (enzyme multiplied immunoassay technique)
c. Fluorescence immunoassay
TDx (Abbott) (fluorescence polarization immunoassay): most common therapeutic
drug monitoring assay
Advantages: simple, automated, highly sensitive, and stable reagents
Disadvantages: background interference attributable to endogenous serum
fluorescence
2. High-pressure liquid chromatography
3. Flame photometry
4. Bioassay
E. Population Pharmacokinetics in Therapeutic Drug Monitoring
1. Population pharmacokinetics useful when:
a. Drug concentrations are obtained during complicated dosing regimens.
b. Drug concentrations are obtained before steady state.
c. Only a few drug concentrations are feasibly obtained (limited sampling strategy).

2. Bayesian pharmacokinetics
a. Prior population information is combined with patient-specific data to predict the most
probable individual parameters.
b. When patient-specific data are limited, there is greater influence from population
parameters; when patient-specific data are extensive, there is less influence.
c. With small amounts of individual data, Bayesian forecasting generally yields more
precise results.

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VIII. PHARMACOKINETICS IN RENAL DISEASE

Patient Cases
9. K.M., an 80-year-old white woman (48 kg, 5'4"), is admitted to the hospital for pyelonephritis with sepsis.
She has a history of myocardial infarction x2, congestive heart failure, hypertension, osteoporosis, rheuma-
toid arthritis, and cerebrovascular accident. On admission, her BUN is 11 mg/dL, her SCr is 0.5 mg/dL, and
her Alb is 2.9 g/dL. K.M. is initiated on the following drugs: trimethoprim-sulfamethoxazole intravenously:
240 mg of trimethoprim every 12 hours; lisinopril 10 mg/day by mouth; digoxin 0.125 mg/day by mouth;
furosemide 40 mg/day by mouth; cimetidine 400 mg by mouth 2 times/day; acetaminophen 325 mg ii by
mouth every 6 hours; calcium carbonate 500 mg by mouth 3 times/day; and carvedilol 6.25 mg by mouth
2 times/day. By the corrected Cockcroft and Gault (C&G) method, which one of the following choices best
estimates K.M.'s CrCl?
A. 64 mL/minute.
B. 75 mL/minute.
C. 102 mL/minute.
D. 120 mL/minute.
10. Which one of K.M.'s drug combinations is most likely to alter her SCr concentrations?
A. Lisinopril and digoxin.
B. Trimethoprim-sulfamethoxazole and cimetidine.
C. Furosemide and calcium carbonate.
D. Acetaminophen and carvedilol.

A. Estimation of Glomerular Filtration Rate (GFR)/CrCl

1. Creatinine production and elimination
a. Creatine is produced in the liver.
b. Creatinine is the product of creatine metabolism in skeletal muscle.
c. Creatinine is filtered at the glomerulus, where it undergoes limited secretion.
d. Creatinine is useful in approximating GFR because
i. At normal concentrations of creatinine, secretion is low.
ii. The creatinine assay picks up a noncreatinine chromogen in the blood but not in the
urine.
2. CrCl calculation to estimate GFR
• CrCl is calculated from a 24-hour urine collection and the following equation:

• Normal CrCl
Healthy young men = 125 mL/minute/1.73 m 2
Healthy young women =115 mL/minute/1.73 m 2
• After age 30, 1% of GFR is lost per year.

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3. CrCl estimation to estimate GFR

a. Factors affecting SCr concentrations:
i. Gender
ii. Age
iii. Weight
iv. Renal function
Caveats:
CrCl estimations worsen as renal function worsens (usually an overestimation).
b. Jeliffe

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 Pharmacokinetics: A Refresher

(a) Corrected C&G equation is normalized to a 72-kg person (similar to most other
estimation equations).
(b) Corrected C&G is not influenced by a patient's weight (it is actually influenced
by height, because the uncorrected equation uses IBW—a function of height).
(c) Corrected C&G (or weight-adjusted C&G) is better to use for estimating renal
function to make dosage adjustments.
e. Modification of diet in renal disease study equation
Full equation:
GFR (mL/minute/1.73 m 2) = 161.5 * (SCr) -0.999 * (age in years) -0.176 * 1.180 (if patient is
African American) * 0.762 (if patient is a woman) * (BUN) -0.170 * (Alb) +0.318
Simplified four-variable equation:
GFR (mL/minute/1.73 m 2) = 175 * (SCr) -1.154 * (age in years) -0.203 * 1.212 (if patient is
African American) * 0.742 (if patient is a woman)
(a) These equations actually directly estimate GFR (NOT CrCl).
(b) These equations are recommended by the American Kidney Foundation and the
European Renal Association to estimate renal function (significantly better than
C&G).
(c) Not as accurate when GFR is greater than 60 mL/minute/1.73 m2
(d) Controversy: rounding up SCr in patients with low concentrations (less than
0.7-1 mg/dL)
f. Chronic Kidney Disease Epidemiology Collaboration equation

Race and Sex Serum Creatinine Equation

(mg/dL)
African American
Female ≤ 0.7 GFR = 166 * (SCr/0.7) -0.329 * (0.993)Age
>0.7 GFR = 166 * (SCr/0.7)-1.209 * (0.993)Age
Male ≤ 0.9 GFR = 163 * (SCr/0.9) -0.411 * (0.993)Age
>0.9 GFR = 163 * (SCr/0.9)-1.209 * (0.993)Age
White or other
Female ≤ 0.7 GFR = 144 * (SCr/0.7)-0.329 * (0.993)Age
>0.7 GFR = 144 * (SCr/0.7)-1.209 * (0.993)Age
Male ≤ 0.9 GFR = 141 * (SCr/0.9)-0.411 * (0.993)Age
>0.9 GFR = 141 * (SCr/0.9)-1.209 * (0.993)Age
GFR = glomerular filtration rate; SCr = serum creatinine.
(a) These equations directly estimate GFR (NOT CrCl).
(b) These equations are more accurate than modification of diet in renal disease at
higher GFRs (i.e., greater than 60 mL/minute/1.73 m2).
(c) Controversy: rounding up SCr in patients with low concentrations (less than
0.7-1 mg/dL)

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 Pharmacokinetics: A Refresher

g. Pediatric formulas
DO NOT round up low SCr values in pediatric patients.
Schwartz
K * ht (cm)
CrCl (mL/minute) =---------------------
SCr
Age K
Low birth weight ≤ 1 year 0.33
Full term ≤ 1 year 0.45
1 year to adolescence 0.55
Muscular adolescent males 0.7

S hu ll

• This is only for those aged 1-18 years.

4. Factors influencing CrCl estimates
a. Patient characteristics
i. Age (decrease, production of creatinine with age)
ii. Female sex (decrease. production of creatinine)
iii. Race ( production of creatinine in African Americans)
b. Disease states/clinical conditions
i. Spinal cord injuries (decrease muscle mass; decrease creatinine)
ii. Amputations (decrease muscle mass; decrease creatinine)
iii. Cushing syndrome (decrease muscle mass; decrease creatinine)
iv. Muscular dystrophy (decrease muscle mass; decrease creatinine)
v. Guillain-Barre syndrome (decrease muscle mass; decrease creatinine)
vi. Rheumatoid arthritis (decrease muscle mass; decrease creatinine)
vii. Liver disease (decrease creatine; decrease creatinine)
viii. Glomerulopathic disease (greater amount of creatinine secretion in relation to filtration)
c. Diet
i. High-meat protein diets ( creatinine ingestion)
ii. Vegetarians (decrease creatinine ingestion)
iii. Protein-calorie malnutrition (decrease creatinine ingestion)
d. Drugs/endogenous substances
i. Laboratory interaction: alkaline picrate method (NOT kinetic alkaline picrate method,
which is more commonly used). Noncreatinine chromogens: in blood but not in urine.
Cephalosporins (especially cefoxitin): chromogenic causing false elevations —much
greater in urine than in blood. Acetoacetate (increased in fasting individuals, patients
with diabetic ketoacidosis): chromogenic causing false elevations
ii. Pharmacokinetic interaction: drugs compete with creatinine for renal secretion
(causing false elevations), trimethoprim, cimetidine, fibric acid derivatives (other
than gemfibrozil), dronedarone

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B. Drug Dosing in Renal Disease

1. Loading dose
a. In general, no alteration is required, but it should be given to hasten achievement of
therapeutic drug concentrations.
b. Alterations in loading dose must occur if the V d is altered secondary to renal dysfunction,
i. Example: digoxin
2. Maintenance dose
a. Alterations should be made in either the dose or the dosing interval.
i. Changing the dosing interval:
(a) Use when the goal is to achieve similar steady-state concentrations.
(b) Less costly
(c) Ideal for limited-dosage forms (i.e., oral medications)
ii. Changing the dose:
(a) Use when the goal is to maintain a steady therapeutic concentration.
(b) More costly
iii. Changing the dose and the dosing interval:
(a) Often required for substantial dosage adjustment with limited-dosage forms
(b) Often required for narrow therapeutic index drugs with target concentrations
(1) If a drug is given more than once daily, then adjust the interval.
(2) If a drug is given once daily or less often, then adjust the dose.

IX. PHARMACOKINETICS IN HEPATIC DISEASE

Patient Case
11. S.J. is a 55-year-old man with hepatic dysfunction and fungemia caused by Candida krusei. He has a small
amount of ascites but is not encephalopathic. He is initiated on caspofungin, and the package insert states
that doses should be decreased in patients with a Child-Pugh score of 7-9. If he has the following hepatic
laboratory values, which one of the following choices is his Child-Pugh score?
Aspartate transaminase = 85 U/L, alanine transaminase = 56 U/L, alkaline phosphatase = 190 U/L, total
bilirubin = 1.8 mg/dL, Alb = 2.9 g/dL, lactic dehydrogenase = 270 U/L, prothrombin time/international
normalized ratio = 14.6/1.7, g-glutamyl transferase = 60 U/L
A. 3.
B. 5.
C. 8.
D. 11.

A. Dosage Adjustment in Hepatic Disease

1. Clinical response is the most important factor in adjusting doses in hepatic disease.
2. Low hepatic extraction ratio drugs
a. Adjustment of maintenance dose is necessary only when hepatic disease alters Cl int .
b. Alterations in protein binding alone do not require alteration of maintenance dose, even
though total drug concentrations decline.

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 Pharmacokinetics: A Refresher

c. Loading doses may require reduction.

3. High hepatic extraction ratio drugs
a. Intravenous administration
i. Usually necessary to decrease maintenance dose rate
ii. Consider effect of hepatic disease on protein binding.
b. Oral administration
i. Usually necessary to decrease maintenance dose rate

B. Rules for Dosing in Hepatic Disease

1. Hepatic elimination of high extraction ratio drugs is more consistently affected by liver
disease than low extraction ratio drugs.
2. The clearance of drugs that are exclusively conjugated is not substantially altered in liver
disease.
Table 2. Child-Pugh Classification for Liver Disease
Points
1 2 3
Encephalopathy 0 1 or 2 3 or 4
Ascites 0 + ++
Bilirubin (mg/dL) < 1.5 1.5-2.3 > 2.3
Alb (g/dL) > 3.5 2.8-3.5 < 2.8
Prothrombin time (seconds over control) 0- 4 4-6 >6
Pugh score: 5 = normal; 6 or 7 = mild (A); 8 or 9 = moderate (B); > 9 = severe (C).
Alb = albumin.

X. PHARMACODYNAMICS
Patient Case
12. Which one of the following is a reason for a drug to follow clockwise hysteresis?
A. Formation of an active metabolite.
B. Delay in equilibrium between the blood and the site of action.
C. Tolerance.
D. Increased sensitivity with time.

A. Definition: relationship between drug concentrations and the pharmacologic response

B. Hill equation

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 Pharmacokinetics: A Refresher

Concentration-response Plot

Figure 5.
C. Hysteresis Loops
Definition: Concentrations late after a dose produce an effect different from that produced by the
same concentration soon after the dose.

Counterclockwise Hysteresis

Causes:
1. Increased sensitivity
2. Formation of an
active metabolite
3. Delay in equilibrium
between plasma
concentrations and
the site of action

Figure 6.

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 Pharmacokinetics: A Refresher

Clockwise Hysteresis

Causes:
1. Tolerance
Effect 2. Formation of an
inhibitory metabolite
3. Equilibrium reached
faster between arterial
blood and site of
action vs. venous
blood and site of
action
Concentration
Figure 7.

Patient Cases
13. P.L., a 45-year-old man with chronic renal failure, is receiving phenytoin 400 mg/day for a history of tonic -
clonic seizures. His phenytoin concentration today is 13.6 mg/L, and his Alb concentration is 4.2 g/dL.
Based on his current concentration, which one of the following choices should be recommended with his
dose?
A. Make no changes to his drug regimen.
B. Keep the total daily dose the same, but change the regimen to 200 mg 2 times/day.
C. Increase the dose for better seizure control.
D. Decrease the dose to prevent toxicity.
14. N.R. is a 63-year-old man with renal insufficiency who comes to the emergency department in atrial fibril-
lation with a ventricular rate of 120 beats/minute. Because of his history of ventricular dysfunction, it is
decided to initiate him on digoxin for rate control. Which one of the following is correct regarding dosing
in this patient?
A. The loading dose should remain the same, but the maintenance dose needs to be decreased.
B. The loading dose needs to be decreased, and the maintenance dose should remain the same.
C. Neither the loading dose nor the maintenance dose needs to be adjusted.
D. Both the loading dose and the maintenance dose need to be decreased.
15. P.P. is a 34-year-old man with a history of cerebral palsy and chronic urinary tract infections. He is admitted
to the hospital with a Psendomonas urinary tract infection that is resistant to all antibiotics but aminogly-
cosides. He is initiated on once-daily tobramycin at 400 mg/day intravenously. Which one of the following
statements best describes this high-dose, extended-interval aminoglycoside regimen?
A. It takes advantage of the concentration-dependent killing of aminoglycoside.
B. It is more efficacious than standard aminoglycoside dosing.
C. It does not require monitoring of aminoglycoside concentrations.
D. It will not cause nephrotoxicity.

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XI. SPECIFIC DRUG TABLE

Table 3.
Drug Therapeutic Range Sampling Issues Comments

Aminoglycosides Cp max = 4-10 mg/L Duration of infusion, timing Be familiar with Sawchuk-Zaske
Amikacin = 20-30 mg/L of first sample postinfusion method and high-dose, extended-
Cp max < 2 mg/L (generally should be 0.5-1 interval dosing
hour)
Amikacin < 10 mg/L
Vancomycin Cp max =10-15 mg/L Controversial whether to Be familiar with changes
(15-20 mg/L for certain obtain peaks or concentrations in trough concentration
infections including altogether recommendations
pneumonia, meningitis, and
osteomyelitis
Phenytoin 10-20 mg/L In general, obtain trough Percent free increases with renal
Free: 1-2 mg/L concentrations failure and hypoalbuminemia;
induces liver enzymes;
susceptible to metabolic drug
interactions
Carbamazepine 4-12 mg/L Autoinduction; active metabolite
10,11 epoxide
Phenobarbital 15-40 mg/L Enzyme inducer
Valproic acid 50-100 mg/L Saturable protein binding;
percent free increases with renal
failure and hypoalbuminemia
Digoxin 0.8-2.0 mcg/L Prolonged distribution period Vd changes with disease states;
necessitates sampling > 6-12 susceptible to drug interactions
hours postdose
Cyclosporine 100-250 mcg/L Whole blood samples Many drug interactions
Lithium 0.3-1.3 mmol/L Prolonged distribution
necessitates sampling 12 hours
postdose

Theophylline 10-20 mg/L Treat as continuous infusion with

sustained-release dosage forms

Cp = concentration of drug plasma.

Table 4. CYP450 Drug Interactions

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REFERENCES
1. Burton ME, Shaw LM, Schentag JJ, eds. Applied
Pharmacokinetics & Pharmacodynamics: Princi-
ples of Therapeutic Drug Monitoring, 4th ed. Balti-
more, MD: Lippincott Williams & Wilkins, 2006.
2. Bauer LA. Clinical pharmacokinetics and pharma-
codynamics. In: DiPiro JT, Talbert RL, Yee GC, et
al., eds. Pharmacotherapy: A Pathophysiologic Ap-
proach, 4th ed. Stamford, CT: Appleton & Lange,
1999:21-43.
3. Winter ME. Basic Clinical Pharmacokinetics, 3rd
ed. Vancouver: Applied Therapeutics, 1994.
4. Bauer LA. Applied Clinical Pharmacokinetics.
New York: McGraw-Hill Medical, 2001.
5. Matheny CJ, Lamb MW, Brouwer KLR, Pollack
GM. Pharmacokinetic and pharmacodynamic im-
plications of P-glycoprotein modulation. Pharma-
cotherapy 2001;21:778-96.

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 Pharmacokinetics: A Refresher
ANSWERS AND EXPLANATIONS TO PATIENT CASES
1. Answer: C
In 6 days (2 t 1/2), the concentration will decrease from
35.9 mg/L to about 9 mg/L; now is the time to redose.
A 1-g dose given on March 24 will increase the concen-
tration in the blood from 12.1 to 35.9 mg/L (12.1 +23.8
mg/L). Given that the t1/2 is about 3 days, it will take
longer than 1 day to reach a concentration of about 10
mg/L. In 3 days (1 t1/2), the concentration will decrease
from 35.9 mg/L to about 18 mg/L—still too early to
redose. Redosing can be figured because plenty of in-
formation exists about how to calculate when to redose.
2. Answer: A
F= (100 mg * 25 mg/L/hour)/ (200 mg * 50 mg/L/hour).
3. Answer: A
The elimination rate constant equals 0.693/4 hours =
0.17 hour 1. The clearance can be calculated by multi-
plying the V d (0.5 L/kg * 65 kg) by the elimination rate
constant. Clearance equals 5.5 L/hour. Concentration
at steady state will equal the infusion rate divided by
clearance. Steady-state concentration = 3.6 mg/L.
4. Answer: D
P-glycoprotein is an efflux pump that pumps drugs
back into the gastrointestinal lumen. P-glycoprotein
is not a plasma protein, and it does not transfer drugs
through the gastrointestinal mucosa but rather pumps
drugs back into the gastrointestinal lumen. In addition,
P-glycoprotein acts in concert with CYP3A4 to dimin-
ish oral absorption.
5. Answer: C
Azithromycin does not inhibit CYP3A4. Erythromycin
and clarithromycin are potent inhibitors of CYP3A4
and would be expected to increase cyclosporine con-
centrations. Cytochrome P450 inhibition is not a drug
class effect.
6. Answer: B
By definition, clearance becomes nonlinear once the
concentration exceeds the Km; therefore, the concen- '
trations will more than double. Phenytoin is not a sig-
nificant autoinducer. Although phenytoin absorption
decreases as the dose is increased, it is not clinically
significant until a single dose exceeds 400 mg.
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7. Answer: C
The correct answer, due to redistribution, is to wait a
few hours to obtain the concentration because it will
increase significantly within the first few hours after
hemodialysis. Waiting a full 24 hours is not necessary.
8. Answer: D
The correct answer is that the assay will be able to dis-
tinguish the drug from like products but will not be able
to detect extremely low concentrations. High specific-
ity means the assay can distinguish the drug from like
products, and low sensitivity means the assay cannot
detect extremely low concentrations.
9. Answer: A
The correct answer is 64 mL/minute because a low SCr
should be rounded up and because the value must be
multiplied by 0.85, given that the patient is a woman.
The other answers are incorrect because the SCr is not
rounded up and because the value is not multiplied by
0.85.
10. Answer: B
Both trimethoprim-sulfamethoxazole and cimetidine
compete with creatinine for secretion in the kidneys,
increasing SCr concentrations. Although angiotensin-
converting enzyme inhibitors may transiently increase
SCr concentrations, digoxin does not affect renal func-
tion. Although furosemide may secondarily affect SCr
concentrations, calcium does not affect renal function.
Acetaminophen and carvedilol generally will not affect
SCr concentrations.
11. Answer: C
S.J. has 1 point for not being encephalopathic, 2 points
for mild ascites, 2 points for the bilirubin concentration,
2 points for the Alb concentration, and 1 point for the
prothrombin time value, for a total of 8 points. Normal
patients have a Child-Pugh score of 5, which means no
hepatic dysfunction.
12. Answer: C
Tolerance leads to a decrease in effect with time; this is
clockwise hysteresis. Formation of an active metabo-
lite, delay in equilibrium between the blood and site of
action, and increased sensitivity with time would all
lead to an increase in effect with time; this is counter-
clockwise hysteresis.
 Pharmacokinetics: A Refresher

13. Answer: D
The dose should be decreased to prevent toxicity. In
renal failure, acidic by-products build up in the blood
and compete with phenytoin for protein binding. Total
concentrations need to be corrected, and this correction
leads to a doubling of the concentration. Therefore, the
current concentration is too high, and the dose should
be decreased. Single doses of 400 mg are fine (doses
higher than 400 mg should be divided).
14. Answer: D
Both the loading dose and the maintenance dose need
to be decreased. In general, loading doses do not need
to be altered in renal dysfunction because they are pri-
marily dependent on the Vd However, the digoxin V d
is decreased in renal dysfunction. Because digoxin is
eliminated renally, the maintenance dose needs to be
decreased.
15. Answer: A
Aminoglycosides show concentration-dependent
killing, and a high-dose, extended-interval amino-
glycoside dose takes advantage of this characteristic.
However, it has not proved to be more efficacious than
traditional dosing. Aminoglycoside concentrations still
need to be monitored with high-dose, extended-interval
therapy. In addition, high-dose, extended-interval ami-
noglycoside dosing can still cause nephrotoxicity (al-
though the incidence is generally diminished).

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ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS
1. Answer: B
With two concentrations, there are enough data to cal-
culate an elimination rate constant and, therefore, a t 1/2
In addition, the V d can be calculated by back extrapola-
tion to the C max and use of appropriate equations (be-
cause this was the first dose, and therefore, it is known
that the tobramycin concentration was 0 mg/L before
the dose was given).
2. Answer: A
The t1/2 is about 2 hours. The C max is about 5 mg/L, and
the Vd, is about 20 L.
3. Answer: B
Her clearance increased because of the improvement
in renal function, which increased her elimination rate
constant and decreased her t1/2 The Vd would not be altered
by changes in clearance (they are independent).
With the diuresis and angiotensin-converting enzyme
inhibitor, her V d probably decreased, but clearance
would not be altered by changes in V d (they are inde-
pendent). In addition, if her V d decreased, her elimina-
tion rate constant would decrease, not increase.
4. Answer: C
Because the trough is too low, the interval will have to
be shortened to increase the concentration. Changes in
dose will have the greatest effect on the peak concen-
tration, and changes in interval will have the greatest
effect on the trough concentration.
5. Answer: C
Her dose needs to be increased, and because she is a
smoker, the interval should be every 8 hours. Doubling
the total daily dose will adequately increase her con-
centration without causing toxic reactions.
6. Answer: D
Because of the patient's renal failure and low Alb, the
total concentration needs to be corrected. The patient's
corrected phenytoin concentration is 14.7 mcg/mL.
Therefore, no changes need to be made to the dose.
7. Answer: C
Both of these are immunoassays. TDx is a brand name
for the Abbott fluorescence polarization immunoassay,
which uses a fluorescent label. The term EMIT stands
for enzyme multiplied immunoassay technique, which
is an immunoassay that uses an enzyme label.
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8. Answer: D
The digoxin concentration was drawn before the dose
taken at 8:00 am had a chance to complete the distri-
bution phase. Once distribution is complete (gener-
ally 6-12 hours after the dose), the concentration will
be lower and probably within the therapeutic range.
Therefore, there is no need for the digoxin antibody,
activated charcoal, or lowering of the dose.
9. Answer: C
The correct statistical test is multiple logistic regres-
sion. Multiple regression is used to describe the rela-
tionship between a dependent variable and two or more
independent variables when both the dependent and in-
dependent variables are numeric. Analysis of variance
is used to describe the relationship between a dependent
variable and two or more independent variables when
the dependent variable is numeric and the independent
variables are nominal. Likewise, analysis of covariance
is used to describe the relationship between a dependent
variable and two or more independent variables when
the dependent variable is numeric and the indepen-
dent variables are nominal with confounding factors.
Spearman rank correlation is a nonparametric test used
to describe the relationship between one dependent and
one independent variable when the data are ordinal or
numeric and not normally distributed.
10. Answer: B
Assessing adherence and increasing her dose, because
the concentration is below the therapeutic range, is
the correct answer. The valproic acid therapeutic range
is 50-100 mg/L, and she is well below this concentra-
tion. Although some patients are controlled at lower
concentrations, this concentration is most likely too
low. She definitely does not need a decrease in dose.
Although total valproic acid concentrations are affected
by changes in Alb, N.T.'s Alb is normal, and obtaining
a free concentration is unnecessary.