Presentation on theme: "Antifungals Julie Duong, Pharm D candidate 2007"— Presentation transcript:
1Antifungals Julie Duong, Pharm D candidate 2007 University of WashingtonSchool of PharmacyJanuary 25, 2007
2Historical facts Most recently approved in October 2006, Posaconazole. DrugApprovalNystatin1954Amphotericin B deoxycholate1958Griseofulvin1959Miconazole, clotrimazole (topical)1969Flucytosine1972Miconazole (IV)1979Ketoconazole1981Fluconazole1990Itraconazole (capsules)1992Terbinafine (topical)1993Terbinafine (oral), ABLC1996ABCD, Liposomal Ampho B, Itraconazole (oral solution)1997Caspofungin2001Voriconazole2002Micafungin2005Anindulafungin2006Historical factsMost recently approved in October 2006, Posaconazole.Note: newer antifungals may have less interactions due to the short time period of being in the market.
3How do they work?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.Image from
4Why is this important?36% of drugs are metabolized by CYP 3A4 and antifungals are largely 3A4 inhibitorsAntifungals can effect up to 60% of all drugs due to inhibition of 3A4, 2C9, 2C19, 1A2.Image from
5Clinical implications Most critical interactions can occur in patients with immunocompromised statusCancer, transplant, HIV, diabetesOn immunosupressant agents which are mostly 3A4 substrates or inducersOn multiple drugsDrug interactions can get complicated.
6GeneMedRxA great clinical resource for dosing medications in complicated situation with drug-drug interactions as well as genetic polymorphisms.
8GeneMedRx before update 19%Algorithm& notesTotal number of interactions = 180154 interactions existed in programNotes & algorithm=30Documented through notes only= 57Correct predictions by algorithm= 65Incorrect algorithm prediction= 137%Detected by notes85%Interaction documented42%AlgorithmUsedonly1% incorrect
9Statistics of updating GeneMedRx 15 antifungals already in system3 drugs were added26 interactions enteredNotes:59 new notes entered19 existing notes modified35 notes added to document predictions by algorithm15%Interaction added
10General causes of interactions with antifungals Decreased absorptionIncrease/decrease plasma levels of other drugsPharmacodynamic interaction
11Polyenes Nystatin No drug interactions found. Mostly topical use and local treatment (oral thrush)Poor systemic absorptionPoor oral bioavailability; no IV formulation
12Polyenes (cont.) Amphotericin B Metabolism not known Excreted by kidney slowly through monthsSide effects include fever, chills, electrolyte abnormalities (↑K,↓Mg), renal dysfunction, and hematologic toxicity.Potential of increasing potassiumRegularly monitor Chem 7 or electrolytes and treat accordinglyCaution when administering with drugs that increase potassium such as thiazide diureticsPotential of increasing nephrotoxicityUse vigorous hydrationAvoid administration with nephrotoxic drugs (cyclosporine, tacrolimus, etc.)Some have suggested alternate day administration—effective???Regularly monitor BUN, Scr, est CrCl, fluid intake and excretion (I&O’s)
13Imidazoles Miconazole Products available are topical and vaginal, negligible topical absorptionSubstrate 3A4Inhibits:Weak: 2B6Moderate: 1A2, 2E1Strong: 2A6, 2C9, 2C19, 2D6, 3A4Interactions occur mostly due to decreased metabolism of 3A4Increase in cyclosporine (↑AUC by 33%), fentanyl, pimozide, tolterodine, and tremetrexate drug levels2C9 interactions: Case reports of increase bleeding with warfarin and increase levels phenytoin.Closely monitor levels
14Imidazole (cont.) Clotrimazole Liver metabolized but not by CYP P450 enzymesInhibits:Weak: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1,Moderate: 3A4Topical, vaginal, oral trocheInteractions primarily through 3A4 inhibition with ergot derivatives, fentanyl, sirolimus, tacrolimus (↑Cmax 2 fold)Monitor drug levels, sedation, etc.
15Imidazole (cont.) Ketoconazole Substrate of CYP3A4 Inhibits: Weak: 2B6, 2C8Moderate: 2A6, 2C19, 2D6Strong: 1A2, 2C9, 3A4Interactions:Decrease absorption due to increase in pH by aluminum, calcium, magnesium containing antacids, PPI, H2 blockersIncreased drug levels of other drugs due to 3A4 inhibitionIncreases risk of QTc prolongationAvoid other QTc inducing drugs (astemizole, etc.) /monitor EKGIncreases risk of rhabdomyolysis when used with statinsMonitor creatine kinase, signs and symptomsExcessive sedation with BZDAlprazolam Cmax↑ slightly; ↓31% clearanceLorazepam is suggested as an alternative.
16TriazolesThis is only a list of the general trends of drug interactions.Refer to GeneMedRx for more details.FluconazoleInhibits:Weak 1A2Moderate 3A4Strong 2C9/19Interactions: Generally same concerns as ketoconazoleItraconazoleSubstrate 3A4Inhibitors:Strong 3A4Interactions: Generally same concerns as ketoconazoleVoriconazoleOral absorption NOT effected by gastric pHSubstrate 2C9/19 major; 3A4 minorSusceptible to 2C19 polymorphisms—no pharmacogenomic dosing suggestedWeak 2C9/19Moderate 3A4 (less than ketoconazole and itraconazole)Interactions: Generally same concerns as ketoconazole except no pH effect
17Triazoles (cont.) Posaconazole UDP Glucuronidated, Pgp 3A4 inhibitor Effected by rifampin , phenytoin (both ↓ Cmax by around 40%)3A4 inhibitorInteractions:Oral absorption NOT effected by gastric pHExcept cimetidine (Cmax↓39%)Increase of other drug levels through 3A4 inhibitionIncreased levels of tacrolimus (Cmax ↑121%), sirolimus, cyclosporine (↑ 29%), midazolam (AUC ↑83%)QTc prolongation
18Allylamines Naftifine Terbinafine Butenafine Only available as a gel or creamPoor systemic absorption 4-6%No interactions found.TerbinafineSubstrate 1A2, 2C9/19, 3A4Cimetidine decreased clearance by 33%Rifampin increased clearance by 100%Avoid combinationInhibitor: 2D6 strongIncreased nortriptyline levels, paroxetine (Cmax↑1.9 fold), amitriptyline (t1/2 ↑ to 400 hrs), desipramine (Cmax ↑ 2 fold).Avoid combination or adjust dosages accordingly.Inducer: 3A4 weakIncreased metabolism of cyclosporine by 15%Monitor cyclosporine levelsButenafineOnly topical use with minimal systemic absorption.
19β-glucan synthase inhibitors CaspofunginMetabolized by hydrolysis and N-acetylationNot inhibitor/inducer/substrate of CYPEnzymes induced by carbamazepine, cyclosporine, dexamethasone, efavirenz, nelfinavir, nevirapine, phenytoin, rifampinDose of Caspo increased to 70mg dailyTacrolimus Cmax reduced by 16%MicafunginSubstrate 3A4 minor; weak inhibitor of 3A4Increased levels of nifedipine Cmax and AUC 42% and 18% and sirolimus AUC 21%Increased monitoring for toxicity and dosage adjustment needed.AnidulafunginDegrades at normal pH and condition to an open-ringed peptideCyclosporine induced AUC 22%Monitor effectiveness in antifungal treatment
20Other Griseofulvin Flucytosine Tolnaftate Liver metabolized Induces 1A2, 2C9, 3A4 weaklyDecreased effectiveness of cyclosporine (↓40%), estrogens, warfarinMonitor effectiveness of treatmentPhenobarbital and omeprazole decreased absorptionMay require increases in doseTheophylline dose reduction when administered with GriseofulvinFlucytosineRenally eliminated unchanged in urine.Interactions:QTc prolongations with Levo Alpha Acetyl MethadoneDecrease in levels due to cytarabine—unknown mechanismIncrease in levels due to amphotericin B—decrease in renal excretion & increase cellular uptakeTolnaftateAvailable as cream, powder, solution, swabs.No interactions found.
21Genetic 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.
22Genetic Polymorphism and 3A4 inhibition #GeneticsNVoriconazole levels (+Ritonavir)1Control20↓Cl 43%; ↑Cmax 17%; ↑ AUC 4.6 fold22C19 *1/*1 Homozygous EM8↓Cl 34%;Cmax NC*; ↑ AUC 1.5 fold32C19 *1/*2 Heterzygous EM↓Cl 45%; ↑Cmax 28%; ↑ AUC 1.9 fold42C19 *2/*2, *2/*3, *3/*3 PM↓Cl 86%; ↑Cmax 30%; ↑ 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.
23Genetic Polymorphism and 3A4 inhibition Tolterodine substrates: 3A4, 2D6 (major)This is a open, nonrandomised, crossover, multiphase study. N=6 whom are 2D6 PM1st 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.2nd 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 givenDay 6,7 only ketoconazole 200mg dailyGeneral results: decrease in oral clearance of tolterodine by 60% and 2.1 fold increase in AUC with concurrent use of ketoconazole
24References 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 Oct;48(4):Drew, RH, et. Al. Overview of Flucytosine. [internet] Wellesley (MA): UpToDate; c2007 [updated 2006,Apr 18;access 2007, Jan 20] Available:He P, et. Al. Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther May;77(5):Luna, B. Overview of Imidazole. [internet] Wellesley (MA): UpToDate; c2007 [updated 2004,Aug 9;access 2007, Jan 20] Available:Luna, B. Overview of Triazoles. [internet] Wellesley (MA): UpToDate; c2007 [updated 2004,Aug 9;access 2007, Jan 20] Available:Mikus G, et al. Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther Aug;80(2): 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 Available at Accessed January***For additional references on specific drug interactions, please refer to GeneMedRx.
25And all the staff at Genelex!! Thank you!Howard ColemanKristine AshcraftJessica OesterheldRichard PattersonAnd all the staff at Genelex!!