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Antifungals

Julie Duong, Pharm D candidate 2007


University of Washington
School of Pharmacy
January 25, 2007

Historical facts
Most recently
approved in October
2006, Posaconazole.
Note: newer
antifungals may
have less
interactions due to
the short time
period of being in
the market.
Drug Approval
Nystatin 1954
Amphotericin B deoxycholate 1958
Griseofulvin 1959
Miconazole, clotrimazole
(topical)
1969
Flucytosine 1972
Miconazole (IV) 1979
Ketoconazole 1981
Fluconazole 1990
Itraconazole (capsules) 1992
Terbinafine (topical) 1993
Terbinafine (oral), ABLC 1996
ABCD, Liposomal Ampho B,
Itraconazole (oral solution)
1997
Caspofungin 2001
Voriconazole 2002
Micafungin 2005
Anindulafungin 2006
How do they work?
Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm
Polyenes, triazoles, and imidazoles
target ergosterol destroying the cell
membranes integrity.

Allylamines inhibit ergosterol
synthesis.

-3-glucan synthase inhibitor block
the production of the -(1,3)-
glucan protein damaging the cell
wall.

Every component of the cell wall
and membrane can be targeted.
Drugs not available in the market
such as Nikkomycin and Polyoxin
target chitin synthase.
Mannoproteins are another
potential target.

Other antifungals such as
flucytosine inhibit DNA/RNA
synthesis and griseofulvin inhibit
fungal cell mitosis preventing cell
proliferation and function.
Why is this important?
36% of drugs are
metabolized by
CYP 3A4 and
antifungals are
largely 3A4
inhibitors
Antifungals can
effect up to
60% of all
drugs due to
inhibition of
3A4, 2C9,
2C19, 1A2.
Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm
Clinical implications
Most critical interactions can occur in
patients with immunocompromised status
Cancer, transplant, HIV, diabetes
On immunosupressant agents which are
mostly 3A4 substrates or inducers
On multiple drugs
Drug interactions can get complicated.
GeneMedRx
A great clinical resource for dosing
medications in complicated situation with
drug-drug interactions as well as genetic
polymorphisms.


Antifungals
Polyenes Imidazoles Triazole
nystatin
amphotericin
B
miconazole
clotrimazole

ketoconazole
fluconazole
itraconazole
voriconazole
posaconazole
Allylamines
naftifine
terbinafine
butenafine
-3-glucan
synthase
inhibitors
caspofungin
micafungin

anidulafungin
Other
griseofulvin
flucytosine
tolnaftate
Classification in GeneMedRx
GeneMedRx before update
Total number of
interactions = 180
154 interactions existed
in program
Notes & algorithm=30
Documented through
notes only= 57
Correct predictions by
algorithm= 65
Incorrect algorithm
prediction= 1
85%
Interaction documented
37%
Detected
by notes
42%
Algorithm
Used
only
1% incorrect
19%
Algorithm
& notes
Statistics of updating GeneMedRx
15 antifungals already in system
3 drugs were added
26 interactions entered
Notes:
59 new notes entered
19 existing notes modified
35 notes added to document
predictions by algorithm
15%
Interaction added
General causes of interactions with
antifungals
Decreased absorption
Increase/decrease plasma levels of other
drugs
Pharmacodynamic interaction



Polyenes
Nystatin
No drug interactions found.
Mostly topical use and local treatment (oral thrush)
Poor systemic absorption
Poor oral bioavailability; no IV formulation

http://akratiri.com/Meds/nystatin_oral.jpeg
Polyenes (cont.)
Amphotericin B
Metabolism not known
Excreted by kidney slowly through months
Side effects include fever, chills, electrolyte abnormalities
(K,Mg), renal dysfunction, and hematologic toxicity.
Potential of increasing potassium
Regularly monitor Chem 7 or electrolytes and treat accordingly
Caution when administering with drugs that increase potassium such as
thiazide diuretics
Potential of increasing nephrotoxicity
Use vigorous hydration
Avoid administration with nephrotoxic drugs (cyclosporine, tacrolimus,
etc.)
Some have suggested alternate day administrationeffective???
Regularly monitor BUN, Scr, est CrCl, fluid intake and excretion (I&Os)
http://poisonevercure.150m.com/New_F
older/amphot1.jpg
Imidazoles
Miconazole
Products available are topical and vaginal, negligible
topical absorption
Substrate 3A4
Inhibits:
Weak: 2B6
Moderate: 1A2, 2E1
Strong: 2A6, 2C9, 2C19, 2D6, 3A4
Interactions occur mostly due to decreased metabolism
of 3A4
Increase in cyclosporine (AUC by 33%), fentanyl, pimozide,
tolterodine, and tremetrexate drug levels
2C9 interactions: Case reports of increase bleeding
with warfarin and increase levels phenytoin.
Closely monitor levels

Imidazole (cont.)
Clotrimazole
Liver metabolized but not by CYP P450 enzymes
Inhibits:
Weak: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1,
Moderate: 3A4
Topical, vaginal, oral troche
Interactions primarily through 3A4 inhibition with
ergot derivatives, fentanyl, sirolimus, tacrolimus
(Cmax 2 fold)
Monitor drug levels, sedation, etc.

Imidazole (cont.)
Ketoconazole
Substrate of CYP3A4
Inhibits:
Weak: 2B6, 2C8
Moderate: 2A6, 2C19, 2D6
Strong: 1A2, 2C9, 3A4
Interactions:
Decrease absorption due to increase in pH by aluminum, calcium,
magnesium containing antacids, PPI, H2 blockers
Increased drug levels of other drugs due to 3A4 inhibition
Increases risk of QTc prolongation
Avoid other QTc inducing drugs (astemizole, etc.) /monitor EKG
Increases risk of rhabdomyolysis when used with statins
Monitor creatine kinase, signs and symptoms
Excessive sedation with BZD
Alprazolam Cmax slightly; 31% clearance
Lorazepam is suggested as an alternative.

Triazoles
This is only a list of the general trends of drug interactions.
Refer to GeneMedRx for more details.
Fluconazole
Inhibits:
Weak 1A2
Moderate 3A4
Strong 2C9/19
Interactions: Generally same concerns as ketoconazole

Itraconazole
Substrate 3A4
Inhibitors:
Strong 3A4
Interactions: Generally same concerns as ketoconazole

Voriconazole
Oral absorption NOT effected by gastric pH
Substrate 2C9/19 major; 3A4 minor
Susceptible to 2C19 polymorphismsno pharmacogenomic dosing suggested
Inhibitors:
Weak 2C9/19
Moderate 3A4 (less than ketoconazole and itraconazole)
Interactions: Generally same concerns as ketoconazole except no pH effect
Triazoles (cont.)
Posaconazole
UDP Glucuronidated, Pgp
Effected by rifampin , phenytoin (both Cmax by around
40%)
3A4 inhibitor
Interactions:
Oral absorption NOT effected by gastric pH
Except cimetidine (Cmax39%)
Increase of other drug levels through 3A4 inhibition
Increased levels of tacrolimus (Cmax 121%), sirolimus,
cyclosporine ( 29%), midazolam (AUC 83%)
QTc prolongation
Allylamines
Naftifine
Only available as a gel or cream
Poor systemic absorption 4-6%
No interactions found.

Terbinafine
Substrate 1A2, 2C9/19, 3A4
Cimetidine decreased clearance by 33%
Rifampin increased clearance by 100%
Avoid combination
Inhibitor: 2D6 strong
Increased nortriptyline levels, paroxetine (Cmax1.9 fold), amitriptyline (t1/2
to 400 hrs), desipramine (Cmax 2 fold).
Avoid combination or adjust dosages accordingly.
Inducer: 3A4 weak
Increased metabolism of cyclosporine by 15%
Monitor cyclosporine levels

Butenafine
Only topical use with minimal systemic absorption.
No interactions found.
-glucan synthase inhibitors
Caspofungin
Metabolized by hydrolysis and N-acetylation
Not inhibitor/inducer/substrate of CYP
Enzymes induced by carbamazepine, cyclosporine, dexamethasone,
efavirenz, nelfinavir, nevirapine, phenytoin, rifampin
Dose of Caspo increased to 70mg daily
Tacrolimus Cmax reduced by 16%
Micafungin
Substrate 3A4 minor; weak inhibitor of 3A4
Increased levels of nifedipine Cmax and AUC 42% and 18% and
sirolimus AUC 21%
Increased monitoring for toxicity and dosage adjustment needed.
Anidulafungin
Not inhibitor/inducer/substrate of CYP
Degrades at normal pH and condition to an open-ringed peptide
Cyclosporine induced AUC 22%
Monitor effectiveness in antifungal treatment
Other
Griseofulvin
Liver metabolized
Induces 1A2, 2C9, 3A4 weakly
Decreased effectiveness of cyclosporine (40%), estrogens, warfarin
Monitor effectiveness of treatment
Phenobarbital and omeprazole decreased absorption
May require increases in dose
Theophylline dose reduction when administered with Griseofulvin

Flucytosine
Renally eliminated unchanged in urine.
Interactions:
QTc prolongations with Levo Alpha Acetyl Methadone
Decrease in levels due to cytarabineunknown mechanism
Increase in levels due to amphotericin Bdecrease in renal excretion & increase
cellular uptake

Tolnaftate
Available as cream, powder, solution, swabs.
No interactions found.
Genetic polymorphism of 3A4
According to a small study (N=26) of
people with 12 genetic variations of 3A4,
no significant alterations in drug
metabolism of Midazolam was found.
A combination of genetic polymorphism of
other enzymes in addition to use of a 3A4
inhibitor may dramatically influence levels
of drugs metabolized by multiple enzymes.
Genetic Polymorphism and 3A4
inhibition
# Genetics N Voriconazole levels
(+Ritonavir)
1 Control 20 Cl 43%; Cmax 17%;
AUC 4.6 fold
2 2C19 *1/*1
Homozygous EM
8 Cl 34%;Cmax NC*;
AUC 1.5 fold
3 2C19 *1/*2
Heterzygous EM
8 Cl 45%; Cmax 28%;
AUC 1.9 fold
4 2C19 *2/*2,
*2/*3, *3/*3 PM
4 Cl 86%; Cmax 30%;
AUC 9 fold
*Not statistically significant; NC No change
This is a randomized, double-blinded, crossover study. Patients were given one dose
of Voriconazole and 4 doses of ritonavir. Levels were measured throughout 48
hours.

Avoid using voriconazole and ritonavir or any potent 3A4 inhibitors in 2C19 PM.
Genetic Polymorphism and 3A4
inhibition
Tolterodine substrates: 3A4, 2D6 (major)
This is a open, nonrandomised, crossover, multiphase study. N=6
whom are 2D6 PM
1
st
phase (N=8)
After washout period of 4 days, each received 4 days of ketoconazole
200mg PO daily and tolterodine 2mg one time on day 2 of ketoconazole
administration.
2
nd
phase (N=6)
After washout period of 3 months, each received 5 doses of
ketoconazole at same dosage as previous and tolterodine 1mg twice
daily for 4.5 days.
Day 3 blood drawn and in the evening received two 1mg loading doses
of tolterodine and ketoconazole.
Day 4,5 ketoconazole 200mg and tolterodine were given
Day 6,7 only ketoconazole 200mg daily
General results: decrease in oral clearance of tolterodine by 60%
and 2.1 fold increase in AUC with concurrent use of ketoconazole
References
Black, D Fall 2007 Pharmacy 560 Antifungal Drugs Lecture.
Brynne N, et al. Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity. Br J
Clin Pharmacol. 1999 Oct;48(4):564-72.
Drew, RH, et. Al. Overview of Flucytosine. [internet] Wellesley (MA): UpToDate; c2007 [updated 2006,Apr 18;access
2007, Jan 20] Available:
http://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKey=antibiot/2067&type=A
&selectedTitle=4~28
He P, et. Al. Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam
clearance in vivo. Clin Pharmacol Ther. 2005 May;77(5):373-87.
Luna, B. Overview of Imidazole. [internet] Wellesley (MA): UpToDate; c2007 [updated 2004,Aug 9;access 2007, Jan 20]
Available:
http://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKey=antibiot/6341&type=A
&selectedTitle=3~66
Luna, B. Overview of Triazoles. [internet] Wellesley (MA): UpToDate; c2007 [updated 2004,Aug 9;access 2007, Jan 20]
Available:
http://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKey=antibiot/9969
Mikus G, et al. Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome
P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther. 2006 Aug;80(2):126-35. Epub 2006 Jul 3.
Product information for Diflucan
Product information for Sporanox
Product information for Grifulvin V
Product information for Vfend
Product information for Eraxis
Product information for Mycamine
Product information for Pinoxifil
Product information for Naftin Gel
Product information for Ketoconazole tablets
Product information for Amphocin
Product information for Lamisil
Thomson Micromedex, Greenwood Village, CL. 2007. Available at http://www.thomsonhc.com. Accessed January 20.
2007.
***For additional references on specific drug interactions, please refer to GeneMedRx.
Thank you!
Howard Coleman
Kristine Ashcraft
Jessica Oesterheld
Richard Patterson
And all the staff at Genelex!!

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