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
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!!