AntifungalsAntifungals

Julie Duong, Pharm D candidate Julie Duong, Pharm D candidate 20072007

University of Washington University of Washington School of PharmacySchool of Pharmacy

January 25, 2007January 25, 2007

Historical Historical factsfacts Most recently Most recently

approved in approved in October 2006, October 2006, Posaconazole.Posaconazole.

Note: newer Note: newer antifungals may antifungals may have less have less interactions due to interactions due to the short time the short time period of being in period of being in the market. the market.

DrugDrug ApprovApprovalal

NystatinNystatin 19541954Amphotericin B Amphotericin B deoxycholatedeoxycholate

19581958

GriseofulvinGriseofulvin 19591959Miconazole, clotrimazole Miconazole, clotrimazole (topical)(topical)

19691969

FlucytosineFlucytosine 19721972Miconazole (IV)Miconazole (IV) 19791979KetoconazoleKetoconazole 19811981FluconazoleFluconazole 19901990Itraconazole (capsules)Itraconazole (capsules) 19921992Terbinafine (topical)Terbinafine (topical) 19931993Terbinafine (oral), ABLCTerbinafine (oral), ABLC 19961996ABCD, Liposomal Ampho B, ABCD, Liposomal Ampho B, Itraconazole (oral solution)Itraconazole (oral solution)

19971997

CaspofunginCaspofungin 20012001VoriconazoleVoriconazole 20022002MicafunginMicafungin 20052005AnindulafunginAnindulafungin 20062006

How do they work?How do they work?

Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htmImage from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Polyenes, triazoles, and imidazoles target ergosterol destroying the cell membrane’s integrity.

Allylamines inhibit ergosterol synthesis.

β-3-glucan synthase inhibitor block the production of the β-(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?Why is this important?36% of drugs are 36% of drugs are

metabolized by metabolized by CYP 3A4 and CYP 3A4 and antifungals are antifungals are largely 3A4 largely 3A4 inhibitorsinhibitors

Antifungals can Antifungals can effect up to effect up to 60% of all 60% of all drugs due to drugs due to inhibition of inhibition of 3A4, 2C9, 3A4, 2C9, 2C19, 1A2.2C19, 1A2.Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htmImage from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Clinical implicationsClinical implications Most critical interactions can occur in Most critical interactions can occur in

patients with immunocompromised patients with immunocompromised statusstatus– Cancer, transplant, HIV, diabetesCancer, transplant, HIV, diabetes– On immunosupressant agents which are On immunosupressant agents which are

mostly 3A4 substrates or inducersmostly 3A4 substrates or inducers– On multiple drugsOn multiple drugs

Drug interactions can get complicated.Drug interactions can get complicated.

GeneMedRxGeneMedRx A great clinical resource for dosing A great clinical resource for dosing

medications in complicated situation medications in complicated situation with drug-drug interactions as well as with drug-drug interactions as well as genetic polymorphisms.genetic polymorphisms.

Antifungals

Polyenes Imidazoles Triazole

nystatin

amphotericin B

miconazole

clotrimazole

ketoconazole

fluconazole

itraconazole

voriconazole

posaconazole

Allylamines

naftifine

terbinafine

butenafine

β-3-glucan synthase inhibitors

caspofungin

micafungin

anidulafungin

Other

griseofulvin

flucytosine

tolnaftate

Classification in GeneMedRxClassification in GeneMedRx

GeneMedRx before updateGeneMedRx before updateTotal number of Total number of interactions = 180interactions = 180– 154 interactions 154 interactions

existed in programexisted in program Notes & algorithm=30Notes & algorithm=30 Documented through Documented through

notes only= 57notes only= 57 Correct predictions by Correct predictions by

algorithm= 65algorithm= 65 Incorrect algorithm Incorrect algorithm

prediction= 1prediction= 1

85% Interaction documented

37%Detecte

d by notes

42%Algorithm

Usedonly

1% incorrect

19%Algorith

m& notes

Statistics of updating Statistics of updating GeneMedRxGeneMedRx

15 antifungals already in system15 antifungals already in system– 3 drugs were added3 drugs were added

26 interactions entered26 interactions entered Notes:Notes:

– 59 new notes entered59 new notes entered– 19 existing notes modified19 existing notes modified– 35 notes added to document 35 notes added to document

predictions by algorithmpredictions by algorithm 15% Interaction added

General causes of interactions General causes of interactions with antifungalswith antifungals

Decreased absorptionDecreased absorption Increase/decrease plasma levels of Increase/decrease plasma levels of

other drugsother drugs Pharmacodynamic interactionPharmacodynamic interaction

PolyenesPolyenes NystatinNystatin

– No drug interactions found.No drug interactions found. Mostly topical use and local treatment (oral Mostly topical use and local treatment (oral

thrush)thrush)– Poor systemic absorptionPoor systemic absorption

Poor oral bioavailability; no IV formulationPoor oral bioavailability; no IV formulation

http://akratiri.com/Meds/nystatin_oral.jpeg

Polyenes (cont.)Polyenes (cont.) Amphotericin BAmphotericin B

– Metabolism not knownMetabolism not known– Excreted by kidney slowly through monthsExcreted by kidney slowly through months– Side effects include fever, chills, electrolyte Side effects include fever, chills, electrolyte

abnormalities (abnormalities (↑K,↓Mg)↑K,↓Mg), renal dysfunction, and , renal dysfunction, and hematologic toxicity. hematologic toxicity. Potential of increasing potassiumPotential of increasing potassium

– Regularly monitor Chem 7 or electrolytes and treat accordinglyRegularly monitor Chem 7 or electrolytes and treat accordingly– Caution when administering with drugs that increase Caution when administering with drugs that increase

potassium such as thiazide diureticspotassium such as thiazide diuretics Potential of increasing nephrotoxicity Potential of increasing nephrotoxicity

– Use vigorous hydrationUse vigorous hydration– Avoid administration with nephrotoxic drugs (cyclosporine, Avoid administration with nephrotoxic drugs (cyclosporine,

tacrolimus, etc.)tacrolimus, etc.) Some have suggested alternate day administration—Some have suggested alternate day administration—

effective???effective???– Regularly monitor BUN, Scr, est CrCl, fluid intake and excretion Regularly monitor BUN, Scr, est CrCl, fluid intake and excretion

(I&O’s)(I&O’s)

http://poisonevercure.150m.com/New_Folder/amphot1.jpg

ImidazolesImidazoles MiconazoleMiconazole

– Products available are topical and vaginal, Products available are topical and vaginal, negligible topical absorptionnegligible topical absorption

– Substrate 3A4 Substrate 3A4 – Inhibits:Inhibits:

Weak: 2B6Weak: 2B6 Moderate: 1A2, 2E1Moderate: 1A2, 2E1 Strong: 2A6, 2C9, 2C19, 2D6, 3A4Strong: 2A6, 2C9, 2C19, 2D6, 3A4

– Interactions occur mostly due to decreased Interactions occur mostly due to decreased metabolism of 3A4metabolism of 3A4 Increase in cyclosporine (Increase in cyclosporine (↑AUC by 33%)↑AUC by 33%), fentanyl, , fentanyl,

pimozide, tolterodine, and tremetrexate drug levelspimozide, tolterodine, and tremetrexate drug levels– 2C9 interactions: Case reports of increase 2C9 interactions: Case reports of increase

bleeding with warfarin and increase levels bleeding with warfarin and increase levels phenytoin.phenytoin. Closely monitor levelsClosely monitor levels

Imidazole (cont.)Imidazole (cont.) ClotrimazoleClotrimazole

– Liver metabolized but not by CYP P450 Liver metabolized but not by CYP P450 enzymesenzymes

– Inhibits:Inhibits: Weak: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, Weak: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, Moderate: 3A4Moderate: 3A4

– Topical, vaginal, oral trocheTopical, vaginal, oral troche– Interactions primarily through 3A4 inhibition Interactions primarily through 3A4 inhibition

with ergot derivatives, fentanyl, sirolimus, with ergot derivatives, fentanyl, sirolimus, tacrolimus (tacrolimus (↑Cmax 2 fold)↑Cmax 2 fold) Monitor drug levels, sedation, etc.Monitor drug levels, sedation, etc.

Imidazole (cont.)Imidazole (cont.) KetoconazoleKetoconazole

– Substrate of CYP3A4Substrate of CYP3A4– Inhibits:Inhibits:

Weak: 2B6, 2C8Weak: 2B6, 2C8 Moderate: 2A6, 2C19, 2D6 Moderate: 2A6, 2C19, 2D6 Strong: 1A2, 2C9, 3A4Strong: 1A2, 2C9, 3A4

– Interactions:Interactions: Decrease absorption due to increase in pH by aluminum, Decrease absorption due to increase in pH by aluminum,

calcium, magnesium containing antacids, PPI, H2 blockerscalcium, magnesium containing antacids, PPI, H2 blockers Increased drug levels of other drugs due to 3A4 inhibitionIncreased drug levels of other drugs due to 3A4 inhibition

– Increases risk of QTc prolongationIncreases risk of QTc prolongation Avoid other QTc inducing drugs (astemizole, etc.) /monitor Avoid other QTc inducing drugs (astemizole, etc.) /monitor

EKGEKG– Increases risk of rhabdomyolysis when used with statinsIncreases risk of rhabdomyolysis when used with statins

Monitor creatine kinase, signs and symptomsMonitor creatine kinase, signs and symptoms– Excessive sedation with BZDExcessive sedation with BZD

Alprazolam CmaxAlprazolam Cmax↑ slightly; ↓31% clearance↑ slightly; ↓31% clearance Lorazepam is suggested as an alternative.Lorazepam is suggested as an alternative.

TriazolesTriazolesThis is only a list of the general trends of drug interactions. This is only a list of the general trends of drug interactions.

Refer to GeneMedRx for more details.Refer to GeneMedRx for more details. FluconazoleFluconazole

– InhibitsInhibits:: Weak 1A2Weak 1A2 Moderate 3A4Moderate 3A4 Strong 2C9/19Strong 2C9/19

– Interactions: Generally same concerns as ketoconazoleInteractions: Generally same concerns as ketoconazole

ItraconazoleItraconazole – Substrate 3A4Substrate 3A4– Inhibitors:Inhibitors:

Strong 3A4Strong 3A4– Interactions: Generally same concerns as ketoconazoleInteractions: Generally same concerns as ketoconazole

VoriconazoleVoriconazole – Oral absorption NOT effected by gastric pHOral absorption NOT effected by gastric pH– Substrate 2C9/Substrate 2C9/1919 major; 3A4 minor major; 3A4 minor

Susceptible to 2C19 polymorphisms—no pharmacogenomic dosing suggestedSusceptible to 2C19 polymorphisms—no pharmacogenomic dosing suggested– InhibitorsInhibitors::

Weak 2C9/19Weak 2C9/19 Moderate 3A4 (less than ketoconazole and itraconazole)Moderate 3A4 (less than ketoconazole and itraconazole)

– Interactions: Generally same concerns as ketoconazole except no pH Interactions: Generally same concerns as ketoconazole except no pH effecteffect

Triazoles (cont.)Triazoles (cont.) PosaconazolePosaconazole

– UDP Glucuronidated, PgpUDP Glucuronidated, Pgp Effected by rifampin , phenytoin (both Effected by rifampin , phenytoin (both ↓↓ Cmax Cmax by by

around 40%)around 40%)– 3A4 inhibitor3A4 inhibitor– Interactions:Interactions:

Oral absorption NOT effected by gastric pHOral absorption NOT effected by gastric pH– Except cimetidine (CmaxExcept cimetidine (Cmax↓39%)↓39%)

Increase of other drug levels through 3A4 inhibitionIncrease of other drug levels through 3A4 inhibition– Increased levels of tacrolimus (Cmax Increased levels of tacrolimus (Cmax ↑121%), sirolimus, ↑121%), sirolimus,

cyclosporine (↑ 29%), midazolam (AUC ↑83%)cyclosporine (↑ 29%), midazolam (AUC ↑83%) QTc prolongationQTc prolongation

AllylaminesAllylamines NaftifineNaftifine

– Only available as a gel or creamOnly available as a gel or cream Poor systemic absorption 4-6%Poor systemic absorption 4-6%

– No interactions found.No interactions found.

TerbinafineTerbinafine– Substrate 1A2, 2C9/19, 3A4Substrate 1A2, 2C9/19, 3A4

Cimetidine decreased clearance by 33%Cimetidine decreased clearance by 33% Rifampin increased clearance by 100%Rifampin increased clearance by 100%

– Avoid combinationAvoid combination– Inhibitor: 2D6 strongInhibitor: 2D6 strong

Increased nortriptyline levels, paroxetine (CmaxIncreased nortriptyline levels, paroxetine (Cmax↑1.9 fold), ↑1.9 fold), amitriptyline (t1/2 ↑ to 400 hrs), desipramine (Cmax ↑ 2 fold).amitriptyline (t1/2 ↑ to 400 hrs), desipramine (Cmax ↑ 2 fold).

– Avoid combination or adjust dosages accordingly.Avoid combination or adjust dosages accordingly.– Inducer: 3A4 weakInducer: 3A4 weak

Increased metabolism of cyclosporine by 15%Increased metabolism of cyclosporine by 15%– Monitor cyclosporine levelsMonitor cyclosporine levels

ButenafineButenafine– Only topical use with minimal systemic absorption.Only topical use with minimal systemic absorption.– No interactions found.No interactions found.

ββ-glucan synthase inhibitors-glucan synthase inhibitors CaspofunginCaspofungin

– Metabolized by hydrolysis and N-acetylationMetabolized by hydrolysis and N-acetylation– Not inhibitor/inducer/substrate of CYPNot inhibitor/inducer/substrate of CYP– Enzymes induced by carbamazepine, cyclosporine, Enzymes induced by carbamazepine, cyclosporine,

dexamethasone, efavirenz, nelfinavir, nevirapine, phenytoin, dexamethasone, efavirenz, nelfinavir, nevirapine, phenytoin, rifampinrifampin

Dose of Caspo increased to 70mg dailyDose of Caspo increased to 70mg daily– Tacrolimus Cmax reduced by 16%Tacrolimus Cmax reduced by 16%

MicafunginMicafungin– Substrate 3A4 minor; weak inhibitor of 3A4Substrate 3A4 minor; weak inhibitor of 3A4– Increased levels of nifedipine Cmax and AUC 42% and 18% Increased levels of nifedipine Cmax and AUC 42% and 18%

and sirolimus AUC 21%and sirolimus AUC 21% Increased monitoring for toxicity and dosage adjustment needed.Increased monitoring for toxicity and dosage adjustment needed.

AnidulafunginAnidulafungin– Not inhibitor/inducer/substrate of CYPNot inhibitor/inducer/substrate of CYP– Degrades at normal pH and condition to an open-ringed Degrades at normal pH and condition to an open-ringed

peptide peptide – Cyclosporine induced AUC 22%Cyclosporine induced AUC 22%

Monitor effectiveness in antifungal treatmentMonitor effectiveness in antifungal treatment

OtherOther GriseofulvinGriseofulvin

– Liver metabolized Liver metabolized – Induces 1A2, 2C9, 3A4 weaklyInduces 1A2, 2C9, 3A4 weakly– Decreased effectiveness of cyclosporine (Decreased effectiveness of cyclosporine (↓40%)↓40%), estrogens, warfarin, estrogens, warfarin

Monitor effectiveness of treatmentMonitor effectiveness of treatment– Phenobarbital and omeprazole decreased absorptionPhenobarbital and omeprazole decreased absorption

May require increases in doseMay require increases in dose– Theophylline dose reduction when administered with GriseofulvinTheophylline dose reduction when administered with Griseofulvin

FlucytosineFlucytosine– Renally eliminated unchanged in urine.Renally eliminated unchanged in urine.– Interactions:Interactions:

QTc prolongations with Levo Alpha Acetyl MethadoneQTc prolongations with Levo Alpha Acetyl Methadone Decrease in levels due to cytarabine—unknown mechanismDecrease in levels due to cytarabine—unknown mechanism Increase in levels due to amphotericin B—decrease in renal excretion & Increase in levels due to amphotericin B—decrease in renal excretion &

increase cellular uptakeincrease cellular uptake

TolnaftateTolnaftate– Available as cream, powder, solution, swabs.Available as cream, powder, solution, swabs.– No interactions found.No interactions found.

Genetic polymorphism of Genetic polymorphism of 3A43A4

According to a small study (N=26) of According to a small study (N=26) of people with 12 genetic variations of people with 12 genetic variations of 3A4, no significant alterations in drug 3A4, no significant alterations in drug metabolism of Midazolam was found.metabolism of Midazolam was found.

A combination of genetic A combination of genetic polymorphism of other enzymes in polymorphism of other enzymes in addition to use of a 3A4 inhibitor may addition to use of a 3A4 inhibitor may dramatically influence levels of drugs dramatically influence levels of drugs metabolized by multiple enzymes.metabolized by multiple enzymes.

Genetic Polymorphism and 3A4 Genetic Polymorphism and 3A4 inhibitioninhibition

## GeneticsGenetics NN Voriconazole levels Voriconazole levels (+Ritonavir)(+Ritonavir)

11 ControlControl 2200

↓↓Cl 43%; ↑Cmax 17%; Cl 43%; ↑Cmax 17%; ↑ AUC 4.6 fold↑ AUC 4.6 fold

22 2C19 *1/*1 2C19 *1/*1 Homozygous Homozygous EMEM

88 ↓↓Cl 34%;Cmax NC*; ↑ Cl 34%;Cmax NC*; ↑ AUC 1.5 foldAUC 1.5 fold

33 2C19 *1/*2 2C19 *1/*2 Heterzygous EMHeterzygous EM

88 ↓↓Cl 45%; ↑Cmax 28%; Cl 45%; ↑Cmax 28%; ↑ AUC 1.9 fold↑ AUC 1.9 fold

44 2C19 *2/*2, 2C19 *2/*2, *2/*3, *3/*3 PM*2/*3, *3/*3 PM

44 ↓↓Cl 86%; ↑Cmax 30%; Cl 86%; ↑Cmax 30%; ↑ AUC 9 fold↑ AUC 9 fold*Not statistically significant; NC No

changeThis 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 Genetic Polymorphism and 3A4 inhibitioninhibition

Tolterodine substrates: 3A4, 2D6 (major)Tolterodine substrates: 3A4, 2D6 (major) This is a open, nonrandomised, crossover, multiphase This is a open, nonrandomised, crossover, multiphase

study. N=6 whom are 2D6 PMstudy. N=6 whom are 2D6 PM 11stst phase (N=8) phase (N=8)

– After washout period of 4 days, each received 4 days of After washout period of 4 days, each received 4 days of ketoconazole 200mg PO daily and tolterodine 2mg one time on ketoconazole 200mg PO daily and tolterodine 2mg one time on day 2 of ketoconazole administration.day 2 of ketoconazole administration.

22ndnd phase (N=6) phase (N=6)– After washout period of 3 months, each received 5 doses of After washout period of 3 months, each received 5 doses of

ketoconazole at same dosage as previous and tolterodine 1mg ketoconazole at same dosage as previous and tolterodine 1mg twice daily for 4.5 days.twice daily for 4.5 days.

– Day 3 blood drawn and in the evening received two 1mg Day 3 blood drawn and in the evening received two 1mg loading doses of tolterodine and ketoconazole.loading doses of tolterodine and ketoconazole.

– Day 4,5 ketoconazole 200mg and tolterodine were givenDay 4,5 ketoconazole 200mg and tolterodine were given– Day 6,7 only ketoconazole 200mg dailyDay 6,7 only ketoconazole 200mg daily

General results: decrease in oral clearance of tolterodine General results: decrease in oral clearance of tolterodine by 60% and 2.1 fold increase in AUC with concurrent use of by 60% and 2.1 fold increase in AUC with concurrent use of ketoconazoleketoconazole

ReferencesReferencesBlack, 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 Drew, RH, et. Al. Overview of Flucytosine. [internet] Wellesley (MA): UpToDate; c2007 [updated 2006,Apr 18;access

2007, Jan 20] Available: 2007, Jan 20] Available: http://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKeyhttp://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKey =antibiot/2067&type==antibiot/2067&type=A&selectedTitleA&selectedTitle=4~28=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 Luna, B. Overview of Imidazole. [internet] Wellesley (MA): UpToDate; c2007 [updated 2004,Aug 9;access 2007, Jan 20] Available: 20] Available: http://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKeyhttp://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKey=antibiot/6341&type==antibiot/6341&type=A&selectedTitleA&selectedTitle=3~66=3~66

Luna, B. Overview of Triazoles. [internet] Wellesley (MA): UpToDate; c2007 [updated 2004,Aug 9;access 2007, Jan 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?20] Available: http://www.uptodateonline.com.offcampus.lib.washington.edu/utd/content/topic.do?topicKey=antibiot/9969topicKey=antibiot/9969

Mikus G, et al. Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome 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.P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther. 2006 Aug;80(2):126-35. Epub 2006 Jul 3.

Product information for DiflucanProduct information for SporanoxProduct information for Grifulvin VProduct information for VfendProduct information for EraxisProduct information for MycamineProduct information for PinoxifilProduct information for Naftin GelProduct information for Ketoconazole tabletsProduct information for AmphocinProduct information for LamisilThomson Micromedex, Greenwood Village, CL. 2007. Available at http://www.thomsonhc.com. Accessed Thomson Micromedex, Greenwood Village, CL. 2007. Available at http://www.thomsonhc.com. Accessed

January 20. 2007.January 20. 2007.***For additional references on specific drug interactions, please refer to GeneMedRx.***For additional references on specific drug interactions, please refer to GeneMedRx.

Thank you!Thank you! Howard ColemanHoward Coleman Kristine AshcraftKristine Ashcraft Jessica OesterheldJessica Oesterheld Richard PattersonRichard Patterson

And all the staff at Genelex!!And all the staff at Genelex!!