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Managing Drug Interactions in the Patient with Aspergillosis

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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., 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 without focal abnormalities.

3 Patient Case Cont. Additional CSF workup: MRI
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 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, metabolism or excretion Pharmacodynamic ∆ of pharmacological effect at standard drug concentrations or ∆ 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 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 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 Azoles are susceptible to pharmacokinetic interactions in the GI tract
Dissolution Aqueous solubility N N N F O H N C H 3 O H 3 C O N N N N N O O N H N N Itraconazole pKa 3.7 log P-5.66 C l C l Fluconazole pKa 2 N N F O H N O H 3 C F Posaconazole pKa 3.6 log P-3 F C H 3 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
CYP3A4 CYP2C8/9 CYP2C19 Drug Inhibitor Substrate Fluconazole2,3 Itraconazole2,3,4 Ketoconazole2,3,5 Voriconazole3,6,7 Posaconazole1 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):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
Effect Alternatives/Management HMG-CoA reductase (lovastatin, simvastatin, atorvastatin) 3-20 fold  Cmax, AUC0-24, t1/2 Fluvastatin, pravastatin, rosuvastin Benzodiazepines (midazolam, triazolam, diazepam) Cmax, AUC, t1/2, F,  clearance Oxazepam, estolazam, temazepam Anxiolytics, sedatives (buspirone) 13-fold  Cmax, AUC0-24 Zolpidem Antipsychotics (Haloperidol)  30% AUC Clozapine 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 AUC Avoid Chemotherapy (Cyclophosphamide, busulfan, vinca alkaloids)  Css > 25-50% Avoid concomitant use, especially for conditioning therapy

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
Effect Alternatives/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 Rifabutin Rifabutin induces metabolism of itraconazole, itraconazole inhibits metabolism of rifabutin Rifabutin uveitis, antifungal efficacy/ itraconazole trough concentrations

16 Voriconazole Interactions Affecting Pharmacokinetics/Dynamics of Other Drugs
(Enzyme) Effect Management 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, NNRTI’s, sirolimus, quinidine and pimozidine, however, published studies are lacking.

17 Posaconazole Interactions Affecting Pharmacokinetics/Dynamics of Other Drugs
Effect Management Immunosuppressants (3A4) • Cyclosporine • Tacrolimus  Cmin 14-24%  AUC 360% Monitor Reduce dose by 50%, monitor Miscellaneous • 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, NNRTI’s, sirolimus, quinidine and pimozidine, however, published studies are lacking.

18 Summary-Important CYP-Azole Interactions
Drug Interaction Azole + Cytochrome P450 Inducers Carbamazepine Phenobarbitol Phenytoin Isoniazid Rifabutin Rifampin Nevirapine Substrate Statins Cyclosporine Tacrolimus Sirolimus Protease inhibitors (saquinavir, ritonavir) Ca2+ channel blockers (diltiazem, verapamil, nifedipine, nisoldipine) 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 Genotype Caucasian Blacks Japanese Chinese Homozygous poor metabolizer 2% 19% 14% Heterozygous extensive metabolizer 26% 28% 46% 43% Homozygous extensive metabolizer 73% 70% 35% Homozygous Extensive metabolizer (n=108) Heterozygous Extensive metabolizer (n=39) Homozygous Poor metabolizer (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 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 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% 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):

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

24 Comparison of the Echinocandin Antifungals- Safety
Caspofungin Micafungin Anidulafungin CYP 3A4 inhibitor? No Drug interactions OATP1B1 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 insufficiency No dosage adjustment Adverse effects Histamine-rxn with infusion, phlebitis, Asymptomatic  transminases Occasional histamine-rxn with infusion, phlebitis, Asymptomatic  transaminases N&V, headache, hypokalemia, and GGT

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 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.


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