Presentation on theme: "Managing Drug Interactions in the Patient with Aspergillosis"— Presentation transcript:
1 Managing Drug Interactions in the Patient with Aspergillosis Russell E. Lewis, Pharm.D., FCCPAssociate ProfessorUniversity of Houston College of Pharmacy/The University of Texas M.D. Anderson Cancer Center
2 Patient Case44 y/o male with myelodysplastic syndrome s/p matched unrelated donor Allo-HSCT (Day +210) admitted with mental status changes and GvHD of the skinRecent 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 therapyNew ground glass opacities and nodular opacities in lower lung lobesDC Ambisome, start voriconazoleReduce tacrolimus dose by 30%On admission:Patient confused, disoriented but responsiveWhole blood tacrolimus 6.9 ng/mL [5-15 ng/mL]Serum electrolytes WNL, CSF normalCT: Moderate parieto-occipital cerebral atrophy without focal abnormalities.
3 Patient Case Cont. Additional CSF workup: MRI Gram stain and cultures negativePCR CMV, HSV 1&2, HHV 6, EBV, Varicella, JC/BKTacrolimusMRIAreas of high signal throughout the white matter particularly involving the parietal regions with some extension on the right to the frontal lobeTacrolimus concentration:Serum 6.2 ng/mLCSF 42 ng/mL!Diagnosis:Tacrolimus associated Posterior Reversible Encephalopathy Syndrome (PRES)Exacerbated by voriconazole?
4 Factors that Increase the Potential for Serious Drug Interactions with Antifungal Therapy PolypharmacyUnderlying renal or hepatic dysfunctionDrugs with narrow therapeutic indexDebilitation /malnutrition/ chronic immunosuppressionGenetic predisposition (I.e. poor metabolizer)Risk is cumulative, and the relative impacteach factor at different timepoints in unknown
5 Classification of Drug Interactions “All drugs known to humans are poisons, only the amount or dose determine the effects.”Paracelsus,Pharmacokinetic∆ in drug absorption, distribution, metabolismor excretionPharmacodynamic∆ of pharmacological effect at standard drug concentrationsor∆ of pharmacological effect resulting from altered pharmacokinetic exposures
6 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 toxicitiesAmphotericin B + other nephrotoxic drugsAmphotericin B nephrotoxicity accumulation of renally-eliminated drugs electrolyte disturbances diuretics enhanced toxicity of steroids digoxin, skeletal muscle relaxantsAzoles + steroids adrenal suppressionAll antifungals hepatic toxicity
7 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 metabolismChanges in hepatic metabolism• Interference with transport proteins• Interference with phase I or II drug metabolismDecreased renal excretion• Interference with glomerular filtration, tubularsecretion or other mechanisms
8 Azoles are susceptible to pharmacokinetic interactions in the GI tract DissolutionAqueous solubilityNNNFOHNCH3OH3CONNNNNOONHNNItraconazolepKa 3.7log P-5.66ClClFluconazolepKa 2NNFOHNOH3CFPosaconazolepKa 3.6log P-3FCH3FVoriconazolepKa 1.63Lipid solubility
10 Hepatic Drug Interactions GeneticDiseaseDietDrugsInfectionOATP (azoles, echinocandins?)Phase I metabolism (CYP P450)(itraconazole, voriconazole)Phase II metabolism (glucoronidation)(posaconazole)Extraction?Metabolism
11 All azoles are inhibitors of CYP Affinities for specific CYP isoforms are drug dependent
12 In Vivo Cytochrome P450 Inhibition Potential vs Other Azoles CYP3A4CYP2C8/9CYP2C19DrugInhibitorSubstrateFluconazole2,3Itraconazole2,3,4Ketoconazole2,3,5Voriconazole3,6,7Posaconazole1Wexler D et al. Eur J Pharm Sci. 2004;21:Cupp MJ et al. Am Fam Phys. 1998;57: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:VFEND [summary of product characteristics]. Kent, UK; Pfizer Ltd; 2005.
13 Itraconazole 3A4 Interactions Affecting Pharmacokinetics of Other Drugs EffectAlternatives/ManagementHMG-CoA reductase(lovastatin, simvastatin, atorvastatin)3-20 fold Cmax, AUC0-24, t1/2Fluvastatin, pravastatin, rosuvastinBenzodiazepines(midazolam, triazolam, diazepam)Cmax, AUC, t1/2, F, clearanceOxazepam, estolazam, temazepamAnxiolytics, sedatives(buspirone)13-fold Cmax, AUC0-24ZolpidemAntipsychotics(Haloperidol) 30% AUCClozapineImmunosuppressantsCsATacrolimus Cmin >50% Cmin 5-foldEmpirically reduce dosage by 50% and monitor levelsCorticosteroidsMethylprednisolone, dexamethazonePrednisolone 3-4x increase in AUC 15-30% increase in t1/2Adrenal-suppressant effectsCalcium channel blockersFelodipine 6-8x fold increase in AUCAvoidChemotherapy(Cyclophosphamide, busulfan, vinca alkaloids) Css > 25-50%Avoid concomitant use, especially for conditioning therapy
14 Cyclophosphamide metabolism is affected by azole antifungals fluconazoleFluconazoleUrineDCCYCYCYP 2B62C9, 2C193A4HCYItraconazoleketoCYHPMMCEPMaldoCYItraconazoleacroleinCyclophosphamide metabolism changes atdifferent dosages (Timmet al Pharmcogenom J 2005;5:365)Marr et al. Blood 2004;103:1557
15 Itraconazole 3A4 Interactions and Anti-Mycobacterial or HIV Drugs EffectAlternatives/ManagementNNRTI(delavirdine, nevirapine, efavirenz)Decreased metabolism of NNRTIs,Nevirapine and efavirenz may induce itraconazole metabolismMonitor for antiviral toxicity and antifungal efficacy/ itraconazole trough concentrationsProtease inhibitors(Indinavir, aprenavir, saquinavir)(lopinavir, ritonavir)Increased PI concentrationsIncreased ITRA concentrationsIndinavir 600 mg q8hMonitor for toxicityRifabutinRifabutin induces metabolism of itraconazole, itraconazole inhibits metabolism of rifabutinRifabutin uveitis, antifungal efficacy/ itraconazole trough concentrations
16 Voriconazole Interactions Affecting Pharmacokinetics/Dynamics of Other Drugs (Enzyme)EffectManagementWarfarin(CYP 2C9)Inhibits primary metabolic pathway, increases PD effect by 41%Monitor INR and adjust dose accordinglyImmunosuppressants(3A4)• Cyclosporin• Tacrolimus• Sirolimus Cmin 248%, AUC 70% CminReduce dose by 50%, monitorReduce dose by 33%, monitorContraindicatedMiscellaneous(2C9, 3A4)• Phenytoin• Omeprazole• Prednisolone• Rifabutin Cmax 70%, AUC 80% Cmax 2.5 fold, AUC 3.8 fold AUC 13-30% AUC, 2-foldMonitor phenytoin levelsReduce dose by 50%MonitorVoriconazole 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 Posaconazole Interactions Affecting Pharmacokinetics/Dynamics of Other Drugs EffectManagementImmunosuppressants(3A4)• Cyclosporine• Tacrolimus Cmin 14-24% AUC 360%MonitorReduce dose by 50%, monitorMiscellaneous• Phenytoin• Rifabutin• Ritonavir AUC 15%, Posa 50% AUC 82%, Posa 50% AUC 30%Monitor phenytoin levelsAvoid if possible, monitor for uveitisClinically 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.
19 Antifungal Serum Drug Concentration Monitoring * Including lipid preparations
20 Distribution of Poor Metabolizers of CYP P450 2C19 in Various Ethnic Groups Influence of CYP2C19 Genotypeon Average Steady-State PlasmaVoriconazole ConcentrationsGenotypeCaucasianBlacksJapaneseChineseHomozygous poor metabolizer2%19%14%Heterozygous extensive metabolizer26%28%46%43%Homozygous extensive metabolizer73%70%35%HomozygousExtensive metabolizer(n=108)HeterozygousExtensive metabolizer(n=39)HomozygousPoormetabolizer(n=8)Clin Pharmacokinet 2002;41:
21 Pharmacogenomic microarray typing- Cleared in U. S Pharmacogenomic microarray typing- Cleared in U.S. and EU for Diagnostic UseCYP450 ArrayThe 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
22 Erythromycin (IV>PO) Antimicrobials and QTc Prolongation- Relative Risk for Torsades de Pointes (TdP)Schedule I: Highest TdP risk, potent Ikr blockers, TdP risk > 1%DofetilideSotalolCisaprideTerbinafineSchedule II: Significant risk for TdP, particularly whenco-administered with CYP inhibitorsClarithromycinErythromycin (IV>PO)SparfloxacinItraconazoleKetoconazolePentamidineSchedule III: Significant risk for TdP, particularlywhen co-administered withCYP inhibitorsGatifloxacinLevofloxacinMoxifloxacinGrepafloxacinGemifloxacin*FluconazoleVoriconazole*Telithromycin*Schedule IV: Low risk for TdP, casereports of TdP, mild Ikr blockade,possible CYP interactionsSchedule V: Questionable/minimalrisk for TdPAzithromycinCotrimoxazoleCiprofloxacin*New antimicrobials, based on post-marketing data may be re-categorizedRC Owens Drugs 2004;64:(10):
23 caspofungin micafungin anidulafungin H N N H O H O H O N H O H N H H N 2NNHOHOHONHOHNHH2NONOHNOHH3CHHCH3CH3CH3HONHOOHHHNOHOHOOHcaspofunginHOOHHOOOHONHH3CNHHON3CH2NNOONHNOHOOHONHOCH3ONHNHOOHOOHSOHOOOOmicafunginanidulafunginHOH3C
24 Comparison of the Echinocandin Antifungals- Safety CaspofunginMicafunginAnidulafunginCYP 3A4 inhibitor?NoDrug interactionsOATP1B1 transporter?Tacrolimus 20%CSA CASPO 35%RIF or other inducers CASPO 30%No effects on tacrolimus,cyclosporine, prednisolone or effects of rifampin. Sirolimus, nifedipine AUC 20%Dosage adjustment in hepatic dysf. To 35 mg/day in moderate hepatic insufficiencyNo dosage adjustmentAdverse effectsHistamine-rxn with infusion, phlebitis,Asymptomatic transminasesOccasional histamine-rxn with infusion, phlebitis,Asymptomatic transaminasesN&V, headache, hypokalemia, and GGT
25 SummaryPatients with invasive aspergillosis have many risk factors for potentially harmful drug interactions, some of which may be unanticipatedA pro-active approach is essential to protect patients from potentially severe interactionsBetter 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 infectionInteractions affecting the QTc (Torsades de pointes)
26 "The person who takes medicine must recover twice, once from the disease and once from the medicine."- William Osler, M.D.