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1 Managing Drug Interactions in the Patient with Aspergillosis Russell E. Lewis, Pharm.D., FCCP Associate Professor University of Houston College of Pharmacy/

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Presentation on theme: "1 Managing Drug Interactions in the Patient with Aspergillosis Russell E. Lewis, Pharm.D., FCCP Associate Professor University of Houston College of Pharmacy/"— Presentation transcript:

1 1 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

2 2 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.

3 3 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?

4 4 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

5 5 All drugs known to humans are poisons, only the amount or dose determine the effects. Paracelsus, 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

6 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 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

7 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 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

8 8 Azoles are susceptible to pharmacokinetic interactions in the GI tract N N N F FOH N NN NN N N N CH 3 F OH F F NNN N N O CH 3 H 3 C O OO C l N N N C l H Fluconazole pK a 2 Voriconazole pK a 1.63 Itraconazole pK a 3.7 log P-5.66 NNN N N O H 3 C O O F N N N F H HO H 3 C Posaconazole pK a 3.6 log P-3 Lipid solubility Aqueous solubility Dissolution

9 9 Gastrointestinal tract drug interactions- Dissolution and Metabolism pH interactions (itraconazole-H2 antagonists, PPI, didanosine, antacids) (posaconazole-cimetidine?) binding interactions (itraconazole-sulcralfate) pH 2 Small intestine pH 5-7 dissolution MDR1 (P-gp) Efflux CYP 3A4 Portal vein OATP Pre-systemic clearance/metabolism (all azoles)

10 10 Hepatic Drug Interactions OATP (azoles, echinocandins?) Phase I metabolism (CYP P450) (itraconazole, voriconazole) Phase II metabolism (glucoronidation) (posaconazole) GeneticDiseaseDietDrugsInfection Extraction?Metabolism

11 11 All azoles are inhibitors of CYP Affinities for specific CYP isoforms are drug dependent

12 12 In Vivo Cytochrome P450 Inhibition Potential vs Other Azoles 1.Wexler 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): Sporanox IV [summary of product characteristics]. Bucks, UK; Janssen-Cilag Ltd; Nizoral tablets [summary of product characteristics]. Bucks, UK; Janssen-Cilag Ltd; Hyland R et al. Drug Metab Dispos. 2003;31: VFEND [summary of product characteristics]. Kent, UK; Pfizer Ltd; CYP3A4CYP2C8/9CYP2C19 Drug InhibitorSubstrateInhibitorSubstrateInhibitorSubstrate Fluconazole 2,3 Itraconazole 2,3,4 Ketoconazole 2,3,5 Voriconazole 3,6,7 Posaconazole 1

13 13 Itraconazole 3A4 Interactions Affecting Pharmacokinetics of Other Drugs DrugEffectAlternatives/Management HMG-CoA reductase (lovastatin, simvastatin, atorvastatin)3-20 fold Cmax, AUC 0-24, t 1/2 Fluvastatin, pravastatin, rosuvastin Benzodiazepines (midazolam, triazolam, diazepam) Cmax, AUC, t 1/2, F, clearance Oxazepam, estolazam, temazepam Anxiolytics, sedatives (buspirone)13-fold Cmax, AUC 0-24 Zolpidem Antipsychotics (Haloperidol) 30% AUCClozapine Immunosuppressants CsA Tacrolimus Cmin >50% Cmin 5-fold Empirically reduce dosage by 50% and monitor levels Corticosteroids Methylprednisolone, dexamethazone Prednisolone 3-4x increase in AUC 15-30% increase in t1/2 Adrenal-suppressant effects Calcium channel blockers Felodipine 6-8x fold increase in AUCAvoid Chemotherapy (Cyclophosphamide, busulfan, vinca alkaloids) C ss > 25-50%Avoid concomitant use, especially for conditioning therapy

14 14 Cyclophosphamide metabolism is affected by azole antifungals CY HCY CYP 2B6 2C9, 2C19 3A4 ketoCY HPMM CEPM Itraconazole DCCYUrine fluconazole aldoCY acrolein Fluconazole Itraconazole Marr et al. Blood 2004;103:1557 Cyclophosphamide metabolism changes at different dosages (Timmet al Pharmcogenom J 2005;5:365)

15 15 Itraconazole 3A4 Interactions and Anti-Mycobacterial or HIV Drugs DrugEffectAlternatives/Management NNRTI (delavirdine, nevirapine, efavirenz) Decreased metabolism of NNRTIs, Nevirapine and efavirenz may induce itraconazole metabolism Monitor for antiviral toxicity and antifungal efficacy/ itraconazole trough concentrations Protease inhibitors (Indinavir, aprenavir, saquinavir) (lopinavir, ritonavir) Increased PI concentrations Increased ITRA concentrations Indinavir 600 mg q8h Monitor for toxicity RifabutinRifabutin induces metabolism of itraconazole, itraconazole inhibits metabolism of rifabutin Rifabutin uveitis, antifungal efficacy/ itraconazole trough concentrations

16 16 Voriconazole Interactions Affecting Pharmacokinetics/Dynamics of Other Drugs Drug (Enzyme) EffectManagement Warfarin (CYP 2C9)Inhibits primary metabolic pathway, increases PD effect by 41% Monitor INR and adjust dose accordingly Immunosuppressants (3A4) Cyclosporin Tacrolimus Sirolimus Cmin 248%, AUC 70% Cmin Reduce dose by 50%, monitor Reduce dose by 33%, monitor Contraindicated Miscellaneous (2C9, 3A4) Phenytoin Omeprazole Prednisolone Rifabutin 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, NNRTIs, sirolimus, quinidine and pimozidine, however, published studies are lacking.

17 17 Posaconazole Interactions Affecting Pharmacokinetics/Dynamics of Other Drugs DrugEffectManagement Immunosuppressants (3A4) Cyclosporine Tacrolimus Cmin 14-24% AUC 360% Monitor Reduce dose by 50%, monitor Miscellaneous (3A4) Phenytoin Rifabutin Ritonavir 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, NNRTIs, sirolimus, quinidine and pimozidine, however, published studies are lacking.

18 18 Summary-Important CYP-Azole Interactions Drug Interaction Azole + Cytochrome P450 Inducers Carbamazepine Phenobarbitol Phenytoin Isoniazid Rifabutin Rifampin Nevirapine Azole + Cytochrome P450 Substrate Statins Cyclosporine Tacrolimus Sirolimus Protease inhibitors (saquinavir, ritonavir) Ca 2+ channel blockers (diltiazem, verapamil, nifedipine, nisoldipine) Azole concentration Substrate concentration

19 19 Antifungal Serum Drug Concentration Monitoring * Including lipid preparations

20 20 Distribution of Poor Metabolizers of CYP P450 2C19 in Various Ethnic Groups Clin Pharmacokinet 2002;41: GenotypeCaucasianBlacksJapaneseChinese Homozygous poor metabolizer 2% 19%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) Influence of CYP2C19 Genotype on Average Steady-State Plasma Voriconazole Concentrations

21 21 Pharmacogenomic microarray typing- Cleared 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

22 22 Antimicrobials and QTc Prolongation- Relative Risk for Torsades de Pointes (TdP) RC Owens Drugs 2004;64:(10): Dofetilide Sotalol Cisapride Terbinafine Clarithromycin Erythromycin (IV>PO) Sparfloxacin Itraconazole Ketoconazole Pentamidine Gatifloxacin Levofloxacin Moxifloxacin Grepafloxacin Gemifloxacin* Fluconazole Voriconazole* Telithromycin* AzithromycinCotrimoxazoleCiprofloxacin Schedule I: Highest TdP risk, potent I kr blockers, TdP risk > 1% Schedule II: Significant risk for TdP, particularly when co-administered with CYP inhibitors *New antimicrobials, based on post-marketing data may be re-categorized Schedule III: Significant risk for TdP, particularly when co-administered with CYP inhibitors Schedule IV: Low risk for TdP, case reports of TdP, mild I kr blockade, possible CYP interactions Schedule V: Questionable/minimal risk for TdP

23 23 anidulafungin N O NH O HO HO NH O OH H N H 2 N OH H 2 N O OH HN OH HO H H H H NH O H CH 3 OH O N H O H 3 C CH 3 CH 3 caspofungin HO O NH O HO OH H N O N HO H 2 N O H 3 C HO NH O HN CH 3 OH N O O OH O NH O O N HOOH O H 3 C S OH O O micafungin

24 Caspofungin MicafunginAnidulafungin CYP 3A4 inhibitor?No Drug 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% No effects on tacrolimus,cyclosporine, prednisolone or effects of rifampin. Dosage adjustment in hepatic dysf. To 35 mg/day in moderate hepatic insufficiency No dosage adjustment Adverse effectsHistamine-rxn with infusion, phlebitis, Asymptomatic transminases Occasional histamine- rxn with infusion, phlebitis, Asymptomatic transaminases N&V, headache, hypokalemia, and GGT Comparison of the Echinocandin Antifungals- Safety

25 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)

26 26 "The person who takes medicine must recover twice, once from the disease and once from the medicine." - William Osler, M.D.


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