Managing Drug Interactions in the Patient with Aspergillosis

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. 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 withoutfocal abnormalities.

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. 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. Pharmacodynamic ∆ of pharmacological effect at standarddrug concentrations or ∆ of pharmacological effect resulting from altered pharmacokinetic exposures Pharmacokinetic ∆ in drug absorption, distribution, metabolism or excretion “All drugs known to humans are poisons, only the amount or dose determine the effects.” Paracelsus, 1490 - 1541 Classification of Drug Interactions

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. 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 Pharmacokinetic Interactions of Antifungals

8. C H 3 H C 3 N N F l l C C C H 3 N N H C 3 N N N F H O N N O O O H N N N N O N H F F C H 3 O H Posaconazole pKa 3.6 log P-3 Azoles are susceptible to pharmacokinetic interactions in the GI tract Dissolution Aqueous solubility N N N O O N N N N N O O N H N Itraconazole pKa 3.7 log P-5.66 N Fluconazole pKa 2 N N F F F Voriconazole pKa 1.63 Lipid solubility

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

10. 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

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 • 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.

13. Itraconazole 3A4 Interactions Affecting Pharmacokinetics of Other Drugs

14. Cyclophosphamide metabolism is affected by azole antifungals Fluconazole fluconazole Urine DCCY CY CYP 2B6 2C9, 2C19 3A4 HCY Itraconazole ketoCY HPMM CEPM aldoCY Itraconazole acrolein Cyclophosphamide metabolism changes at different 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

16. Voriconazole Interactions Affecting Pharmacokinetics/Dynamics of Other Drugs 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.

17. Posaconazole Interactions Affecting Pharmacokinetics/Dynamics of Other Drugs 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.

18. Summary-Important CYP-Azole Interactions Azole concentration Substrate concentration

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 Genotype on Average Steady-State Plasma Voriconazole Concentrations Homozygous Extensive metabolizer (n=108) Heterozygous Extensive metabolizer (n=39) Homozygous Poor metabolizer (n=8) Clin Pharmacokinet 2002;41:913-958.

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. Antimicrobials and QTc Prolongation-Relative Risk for Torsades de Pointes (TdP) Schedule I: Highest TdP risk, potent Ikr blockers, TdP risk > 1% Dofetilide Sotalol Cisapride Terbinafine Schedule II: Significant risk for TdP, particularly when co-administered with CYP inhibitors Clarithromycin Erythromycin (IV>PO) Sparfloxacin Itraconazole Ketoconazole Pentamidine Schedule III: Significant risk for TdP, particularly when co-administered with CYP inhibitors Gatifloxacin Levofloxacin Moxifloxacin Grepafloxacin Gemifloxacin* Fluconazole Voriconazole* Telithromycin* Schedule IV: Low risk for TdP, case reports of TdP, mild Ikr blockade, possible CYP interactions Schedule V: Questionable/minimal risk for TdP Azithromycin Cotrimoxazole Ciprofloxacin *New antimicrobials, based on post-marketing data may be re-categorized RC Owens Drugs 2004;64:(10):1091-1124.

23. H N 2 H O O H O O H O N H O H N H C H 3 H O N H N H N O N H O H C H N O H 3 H N 2 O H H N H C 3 H O N H O H C 3 C H C H 3 3 C H 3 N H H O N O O H H N H O N C H 3 O H O H O H O H O O H H O O H H O N H H O H O H C 3 N H H N 2 H N O H H O N H C H 3 H N H O O H O H O H H O H C 3 O O H O N O H H O H H O O caspofungin O O N O N O O O O N O O O S O O O micafungin anidulafungin

24. 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 alwayssignificant: • 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 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.