Managing Drug Interactions in the Patient with Aspergillosis

Managing Drug Interactions in the Patient with Aspergillosis Russell E. Lewis, Pharm.D., FCCP Associate Professor University of Houston College of Pharmacy/ The University of Texas M.D. Anderson Cancer Center 1 Patient Case  44 y/o male with myelodysplastic syndrome s/p matched unrelated donor Allo-HSCT (Day +210) admitted with mental status changes and GvHD of the skin  Recent PMH:  Ambisome 5 mg/kg 3x weekly, valganciclovir (maint dose), levofloxacin, TMP/sulfa prophylaxis, and vancomycin (catheter infection)  Extensive flair of GvHD involving skin, started on steroids in addition to current tacrolimus therapy  New ground glass opacities and nodular opacities in lower lung lobes  DC Ambisome, start voriconazole  Reduce tacrolimus dose by 30%  On admission:     Patient confused, disoriented but responsive Whole blood tacrolimus 6.9 ng/mL [5-15 ng/mL] Serum electrolytes WNL, CSF normal CT: Moderate parieto-occipital cerebral atrophy without focal abnormalities. 2 Patient Case Cont.  Additional CSF workup:  Gram stain and cultures negative  PCR CMV, HSV 1&2, HHV 6, EBV, Varicella, JC/BK  Tacrolimus  MRI  Areas of high signal throughout the white matter particularly involving the parietal regions with some extension on the right to the frontal lobe  Tacrolimus concentration:  Serum 6.2 ng/mL  CSF 42 ng/mL!  Diagnosis:  Tacrolimus associated Posterior Reversible Encephalopathy Syndrome (PRES)  Exacerbated by voriconazole? 3 Factors that Increase the Potential for Serious Drug Interactions with Antifungal Therapy      Polypharmacy Underlying renal or hepatic dysfunction Drugs with narrow therapeutic index Debilitation /malnutrition/ chronic immunosuppression Genetic predisposition (I.e. poor metabolizer) Risk is cumulative, and the relative impact each factor at different timepoints in unknown 4 Classification of Drug Interactions Pharmacokinetic ∆ in drug absorption, distribution, metabolism or excretion Pharmacodynamic ∆ of pharmacological effect at standard drug concentrations or ∆ of pharmacological effect resulting from altered pharmacokinetic exposures “All drugs known to humans are poisons, only the amount or dose determine the effects.” Paracelsus, 1490 - 1541 5 Pharmacodynamic Interactions of Antifungals  Beneficial:  Synergy (e.g., echinocandin + triazole)  Suppression of resistance (e.g., 5-FC + amphotericin B)  Detrimental:  Antagonism (e.g., triazole + amphotericin B)  Overlapping toxicities  Amphotericin B + other nephrotoxic drugs  Amphotericin B nephrotoxicity  accumulation of renally-eliminated drugs  electrolyte disturbances  diuretics  enhanced toxicity of steroids  digoxin, skeletal muscle relaxants  Azoles + steroids  adrenal suppression  All antifungals  hepatic toxicity 6 Pharmacokinetic Interactions of Antifungals Decreased absorption from GI tract • Alterations in pH • Complex formation with ions • Interference w/transport protein (i.e. P-gp) • Pre-systemic enteric metabolism Changes in hepatic metabolism • Interference with transport proteins • Interference with phase I or II drug metabolism Decreased renal excretion • Interference with glomerular filtration, tubular secretion or other mechanisms 7 Azoles are susceptible to pharmacokinetic interactions in the GI tract Dissolution Aqueous solubility N N N N N N N OH F N N N N N O O F H3C CH3 N N N N OH F N N O O N H Cl Cl Fluconazole pKa 2 Itraconazole pKa 3.7 log P-5.66 H3C F H3C N HO N N N O O O N N N F CH3 Voriconazole pKa 1.63 N H F F Posaconazole pKa 3.6 log P-3 Lipid solubility 8 Gastrointestinal tract drug interactionsDissolution and Metabolism pH 2 pH interactions (itraconazole-H2 antagonists, PPI, didanosine, antacids) (posaconazole-cimetidine?) binding interactions (itraconazole-sulcralfate) dissolution Pre-systemic clearance/metabolism (all azoles) Small intestine pH 5-7 MDR1 (P-gp) Efflux CYP 3A4 OATP Portal vein 9 Hepatic Drug Interactions Genetic Disease Diet Drugs Infection OATP (azoles, echinocandins?) Phase I metabolism (CYP P450) (itraconazole, voriconazole) Phase II metabolism (glucoronidation) (posaconazole) Extraction? Metabolism 10 All azoles are inhibitors of CYP Affinities for specific CYP isoforms are drug dependent 11 In Vivo Cytochrome P450 Inhibition Potential vs Other Azoles CYP3A4 Drug Fluconazole2,3 Itraconazole2,3,4 Ketoconazole2,3,5 Voriconazole3,6,7 Posaconazole1 1. 2. 3. 4. 5. 6. 7. CYP2C8/9 Inhibitor Substrate CYP2C19 Inhibitor Substrate Inhibitor Substrate              Wexler D et al. Eur J Pharm Sci. 2004;21:645-653. Cupp MJ et al. Am Fam Phys. 1998;57:107-116. Drug interactions. Med Letter. 2003;45(W1158B):46-48. Sporanox IV [summary of product characteristics]. Bucks, UK; Janssen-Cilag Ltd; 2005. Nizoral tablets [summary of product characteristics]. Bucks, UK; Janssen-Cilag Ltd; 2001. Hyland R et al. Drug Metab Dispos. 2003;31:540-547. VFEND [summary of product characteristics]. Kent, UK; Pfizer Ltd; 2005. 12 Itraconazole 3A4 Interactions Affecting Pharmacokinetics of Other Drugs Drug HMG-CoA reductase (lovastatin, simvastatin, atorvastatin) Benzodiazepines (midazolam, triazolam, diazepam) Anxiolytics, sedatives (buspirone) Antipsychotics (Haloperidol) Immunosuppressants CsA Tacrolimus Corticosteroids Methylprednisolone, dexamethazone Prednisolone Calcium channel blockers Felodipine Effect Alternatives/Management 3-20 fold  Cmax, AUC0-24, t1/2 Cmax, AUC, t1/2, F,  clearance 13-fold  Cmax, AUC0-24 Fluvastatin, pravastatin, rosuvastin Oxazepam, estolazam, temazepam Zolpidem  30% AUC  Cmin >50%  Cmin 5-fold  3-4x increase in AUC  15-30% increase in t1/2  6-8x fold increase in AUC  Css > 25-50% Clozapine Empirically reduce dosage by 50% and monitor levels Adrenal-suppressant effects Avoid Avoid concomitant use, especially for conditioning therapy Chemotherapy (Cyclophosphamide, busulfan, vinca alkaloids) 13 Cyclophosphamide metabolism is affected by azole antifungals Urine DCCY fluconazole Fluconazole CY HCY ketoCY HPMM CEPM CYP 2B6 2C9, 2C19 3A4 Itraconazole Itraconazole aldoCY acrolein Cyclophosphamide metabolism changes at different dosages (Timmet al Pharmcogenom J 2005;5:365) Marr et al. Blood 2004;103:1557 14 Itraconazole 3A4 Interactions and Anti-Mycobacterial or HIV Drugs Drug NNRTI (delavirdine, nevirapine, efavirenz) Effect Alternatives/Management Decreased metabolism of NNRTIs, Nevirapine and efavirenz may induce itraconazole metabolism Increased PI concentrations Increased ITRA concentrations Rifabutin induces metabolism of itraconazole, itraconazole inhibits metabolism of rifabutin Monitor for antiviral toxicity and antifungal efficacy/ itraconazole trough concentrations Protease inhibitors (Indinavir, aprenavir, saquinavir) (lopinavir, ritonavir) Rifabutin Indinavir 600 mg q8h Monitor for toxicity Rifabutin uveitis, antifungal efficacy/ itraconazole trough concentrations 15 Voriconazole Interactions Affecting Pharmacokinetics/Dynamics of Other Drugs Drug (Enzyme) Warfarin (CYP 2C9) Effect Management Inhibits primary metabolic pathway, increases PD effect by 41% Monitor INR and adjust dose accordingly Immunosuppressants (3A4) • Cyclosporin • Tacrolimus • Sirolimus Miscellaneous (2C9, 3A4) • Phenytoin • Omeprazole • Prednisolone • Rifabutin  Cmin 248%, AUC 70%  Cmin  Cmin Reduce dose by 50%, monitor Reduce dose by 33%, monitor Contraindicated  Cmax 70%, AUC 80%  Cmax 2.5 fold, AUC 3.8 fold  AUC 13-30%  AUC, 2-fold Monitor phenytoin levels Reduce dose by 50% Monitor Voriconazole may also increase the plasma concentrations of several drugs including benzodizepines, calcium channel blockers, HMG-CoA reductase inhibitors, vinca alkaloids, busulfan, cyclophosphamide sulfonylureas, protease inhibitors, NNRTI’s, sirolimus, quinidine and pimozidine, however, published studies are lacking. 16 Posaconazole Interactions Affecting Pharmacokinetics/Dynamics of Other Drugs Drug Immunosuppressants (3A4) • Cyclosporine • Tacrolimus Miscellaneous (3A4) • Phenytoin • Rifabutin • Ritonavir Effect Management  Cmin 14-24%  AUC 360% Monitor Reduce dose by 50%, monitor  AUC 15%, Posa  50%  AUC 82%, Posa  50%  AUC 30% Monitor phenytoin levels Avoid if possible, monitor for uveitis Clinically significant? Posaconazole may also increase the plasma concentrations of several drugs including benzodizepines, calcium channel blockers, HMG-CoA reductase inhibitors, vinca alkaloids, busulfan, cyclophosphamide, sulfonylureas, protease inhibitors, NNRTI’s, sirolimus, quinidine and pimozidine, however, published studies are lacking. 17 Summary-Important CYP-Azole Interactions Drug Interaction Azole + Cytochrome P450 Inducers Carbamazepine Phenobarbitol Phenytoin Isoniazid Rifabutin Rifampin Nevirapine Azole concentration Azole + Cytochrome P450 Substrate Statins Cyclosporine Tacrolimus Sirolimus Substrate concentration Protease inhibitors (saquinavir, ritonavir) Ca2+ channel blockers (diltiazem, verapamil, nifedipine, nisoldipine) 18 Antifungal Serum Drug Concentration Monitoring Agent Amphotericin B* Flucytosine Fluconazole Itraconazole Justified in select situations? No Yes- toxicity No Yes-ensure absorption, efficacy Yes-variable metabolism associated with sub-therapeutic and toxic concentrations  drug interactions, pediatrics? Yes, ensure absorption, efficacy No Target Range N/A < 100 mcg/mL N/A > 0.5 mcg/mL Timing of Sample N/A 2 hour postdose peak N/A Trough after 7 days of therapy Trough after 7 days of therapy Voriconazole 1-2 to 6 mcg/mL Posac onazole > 0.25 mcg/mL? N/A Echinocandins Trough after 7 days of therapy N/A 19 * Including lipid preparations Distribution of Poor Metabolizers of CYP P450 2C19 in Various Ethnic Groups Influence of CYP2C19 Genotype on Average Steady-State Plasma Voriconazole Concentrations Genotype Homozygous poor metabolizer Caucasian 2% Blacks 2% Japanese 19% Chinese 14% Heterozygous extensive metabolizer 26% 28% 46% 43% Homozygous extensive metabolizer 73% 70% 35% 43% Homozygous Extensive metabolizer (n=108) Heterozygous Extensive metabolizer (n=39) Homozygous Poor metabolizer (n=8) Clin Pharmacokinet 2002;41:913-958. 20 Pharmacogenomic microarray typingCleared in U.S. and EU for Diagnostic Use CYP450 Array The world's first pharmacogenomic microarray designed for clinical applications that provides comprehensive coverage of gene variations – including deletions and duplications – for the 2D6 and 2C19 genes, which play a role in the metabolism of about 25% of all prescription drugs. It is intended to be an aid for physicians in individualizing treatment doses for patients on therapeutics metabolized through these genes. Cost- ~ $500/ test 21 Antimicrobials and QTc ProlongationRelative Risk for Torsades de Pointes (TdP) Schedule I: Highest TdP risk, potent Ikr blockers, TdP risk > 1% Dofetilide Sotalol Schedule II: Significant risk for TdP, particularly when co-administered with CYP inhibitors Cisapride Terbinafine Clarithromycin Erythromycin (IV>PO) Sparfloxacin Itraconazole Ketoconazole Pentamidine Schedule III: Significant risk for TdP, particularly when co-administered with CYP inhibitors Schedule IV: Low risk for TdP, case reports of TdP, mild Ikr blockade, possible CYP interactions Schedule V: Questionable/minimal risk for TdP Gatifloxacin Levofloxacin Moxifloxacin Grepafloxacin Gemifloxacin* Fluconazole Voriconazole* Telithromycin* Azithromycin Cotrimoxazole Ciprofloxacin 22 *New antimicrobials, based on post-marketing data may be re-categorized RC Owens Drugs 2004;64:(10):1091-1124. H2N NH O HO NH OH O H H2N N O O HN H H HO O OH NH H O H N H N H OH H3C CH3 CH3 CH3 OH O OH caspofungin HO HO O NH H3C H2N N O O HO NH O N H N HO O OH OH O O OH HO H N NH O N H3C O CH3 O CH3 HN NH HO OH O NH OH O HO HO O OH O N O H3C N H3C O HN NH O OH O HO OH O S O O OH HO micafungin HO H3C anidulafungin 23 Comparison of the Echinocandin AntifungalsSafety Caspofungin CYP 3A4 inhibitor? No Micafungin No Anidulafungin No Drug interactions OATP1B1 transporter? Tacrolimus 20% CSA  CASPO 35% RIF or other inducers  CASPO 30%  To 35 mg/day in moderate hepatic insufficiency No effects on tacrolimus,cyclosporine, prednisolone or effects of rifampin.  Sirolimus, nifedipine AUC 20% No dosage adjustment No effects on tacrolimus,cyclosporine, prednisolone or effects of rifampin. Dosage adjustment in hepatic dysf. No dosage adjustment Adverse effects Histamine-rxn with infusion, phlebitis, Asymptomatic  transminases Occasional histaminerxn with infusion, phlebitis, Asymptomatic  transaminases N&V, headache, hypokalemia, and GGT Summary • Patients with invasive aspergillosis have many risk factors for potentially harmful drug interactions, some of which may be unanticipated • A pro-active approach is essential to protect patients from potentially severe interactions – Better laboratory support may help the management of suspected interactions (serum drug level monitoring, genotyping?) • Drug interactions that are always significant: – Interactions affecting agents with narrow therapeutic index (e.g., immunosuppressants, chemotherapy, anti-retrovirals) – Interactions increasing the metabolism of antifungals used to treat the Aspergillus infection – Interactions affecting the QT c (Torsades de pointes) "The person who takes medicine must recover twice, once from the disease and once from the medicine." - William Osler, M.D. 26