Managing Drug Interactions in Hepatitis C: A Case-Based Approach

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1 Managing Drug Interactions in Hepatitis C: A Case-Based Approach Alice Tseng PharmD, FCSHP, AAHIVP Toronto General Hospital May 30 th, 2012 Objectives Review principles of drug interactions Understand how the pharmacology of DAAs contribute to drug interactions Outline a strategy for identifying and managing drug interactions Highlight pertinent HCV drug interaction resources Drug Interactions Pharmacodynamic change in pharmacological effect of a drug additive, synergistic, or antagonistic activity or toxicity e.g., ribavirin + AZT = anemia Pharmacokinetic change in the amount of drug(s) in body absorption, distribution, metabolism, elimination may be affected often involves CYP450 system or transporters Cytochrome P450 Enzymes Superfamily of microsomal heme-containing enzymes which chemically oxidize or reduce drugs and endogenous substances primarily located in liver, small bowel; also kidney, lung, brain regulate rate and extent of drug breakdown in the body Classified into families and subfamilies three main CYP families: 1, 2, 3 Proportion of Drugs Metabolized by the Major CYP450 Enzymes CYP2D6 CYP2C CYP1A2 CYP2E1 CYP3A CYP3A CYP2D6 CYP2C CYP1A2 CYP2E1 Boceprevir and Telaprevir Pharmacology Substrate Inhibits Induces CYP3A4, P-glycoprotein AKR1C2/3 (BOC) CYP3A4, P-glycoprotein Renal transporters (? TVR) Possible = +++ potential for interactions with other drugs can be clinically significant sometimes unpredictable

2 Why Drug Concentrations Matter DAAs: food-dependent absorption short t1/2 CYP3A4, Pgp substrates adequate exposures required for efficacy Statin Interactions Most statins are P450 substrates atorvastatin, lovastatin, simvastatin: CYP3A4 rosuvastatin: <1 metabolized; 2C9, 2C19, Pgp? pravastatin: 40-54% Clrenal; CYP3A(?), OATP1B1, OATP2B1 fluvastatin: CYP2C9 >>3A4 (minor) BOC & TVR can significantly statin levels risk of toxicity, including myopathy and rhabdomyolysis Anderson P. The ABCs of Pharmacokinetics. thebody.com, 2005 Pharmacokinetic Interaction Between Boceprevir 800 mg TID and Single-Dose Atorvastatin or Pravastatin in Healthy Volunteers Atorvastatin 40 mg + BOC: atorvastatin AUC 13 and Cmax 17 vs atorvastatin alone Suggest atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin Pravastatin 40 mg + BOC: pravastatin AUC 6 and Cmax 5 vs pravastatin alone Can initiate pravastatin at the recommended dose when coadministered with BOC, with close clinical monitoring. [Hulskotte EGJ et al. HEP DART 2011, Koloa, Hawaii, poster 122.] Effect of Steady-State Telaprevir on the Pharmacokinetics of Atorvastatin Single dose atorvastatin 20 mg in presence of telaprevir 750 mg q8h: atorvastatin AUC 7.88-fold Combination is contraindicated [Lee et al. Antimicrob Agents Chemother 2011, 55(10): ] How To Manage Drug Interactions Options depend upon: disease(s) being treated therapeutic index of drug(s) availability of other alternatives patient-specific factors

3 Managing Inhibition Interactions Using Statins with Boceprevir or Telaprevir Possible to temporarily d/c drug? Boceprevir Telaprevir Dose adjustment of one/both drugs alter dose and/or frequency Replace drug with another agent with less interaction potential e.g., clarithromycin azithromycin Therapeutic drug monitoring (if available) Clinical monitoring (effect/toxicity) quick onset/resolution of interaction Lovastatin, Simvastatin Atorvastatin Pravastatin Rosuvastatin, Fluvastatin May need to atorvastatin dose; do not exceed >20 mg/d CONTRAINDICATED Start with recommended dose and monitor for toxicity. CONTRA-INDICATED Possible in statin; use with caution. Possible in statin; use with caution. Use lowest statin dose and titrate slowly to response [Victrelis & Incivek Product Monographs, FDA HIV/AIDS Drug Safety Communication, March 1, 2012] Midazolam (Versed ) Interactions Midazolam is a CYP3A4 substrate 5 to 9-fold AUC with boceprevir or telaprevir using oral midazolam Midazolam (oral) is contraindicated with HCV protease inhibitors IV midazolam: 3.4-fold AUC with telaprevir; no data with BOC consider dose, close monitoring for respiratory depression or prolonged sedation Alternatives: lorazepam (Ativan) or propofol (Diprivan) [ Victrelis & Incivek Product Monographs, 2011] Potential Interactions Effect of Steady-State Telaprevir on the Pharmacokinetics of Amlodipine 5 mg CYP3A4 substrates: atorvastatin amlodipine fluticasone tadalafil amlodipine AUC 179% monitor for dose-related toxicity [Lee et al. Antimicrob Agents Chemother 2011, 55(10): ]

4 Corticosteroids Interactions Corticosteroids are CYP3A4 substrates fluticasone has receptor binding t1/2 & Vd vs. other inhaled corticosteroids, more adrenal suppression Inhaled/nasal fluticasone, budesonide: Potential for corticosteroid concentrations resulting in significantly reduced serum cortisol concentrations. Avoid co-administration with HCV PIs if possible, particularly for extended durations. Systemic dexamethasone: Potential for DAA concentrations via CYP3A4 induction. Avoid combination if possible, use with caution if necessary. [Victrelis & Incivek Product Monographs, 2011] Adrenal Suppression/Cushing s due to Corticosteroid/HIV Protease Interactions Triamcinolone injections: 8 cases intra-articular (n=6), epidural (n=1) or intra-muscular (n=1) injection onset: within 2 weeks after single injection Corticosteroid eye drops: 1 case dexamethasone 0.1% eye drops 6x/d and betamethasone 0.1% eye ointment qhs for >8 months [Dort et al. AIDS Res Ther 2009 Jun 8;6(1):10. Ramanathan et al. Clin Infect Dis Dec 15;47(12):e97-9. Yombi et al. Clin Rheumatol 2008 Dec;27 Suppl 2:S Danaher et al. Orthopedics 2009;32(6):450. Molloy et al. AIDS 2011;25:1337 9] Managing/Avoiding Interactions with Corticosteroids Suggested corticosteroid alternatives: inhaled: beclomethasone (QVAR), ciclesonide (Alvesco) intranasal: beclomethasone (Rhinavase), triamcinolone (Nasacort) caution still warranted since all are CYP3A4 substrates Use lowest possible dose in patients on any DAA and monitor closely for Cushingoid adverse effects Consider non-steroidal options (e.g., oral montelukast/singulair, tiotropium/spiriva ) Routinely screen for use of steroids at each visit Dosing of PDE5 Inhibitors with DAAs For PAH: Sildenafil (Revatio ) Tadalafil (Adcirca ) Usual Dose 20 mg TID 40 mg QD With DAA Contraindicated Contraindicated (BOC); Not recommended (TVR) For ED: (Viagra ) (Cialis ) Vardenafil (Levitra ) Usual Dose mg QD mg QD (on demand) With DAA 25 mg q48h 10 mg q72h, max 3x/week [Victrelis Product Monograph, July 2011; Incivek Product Monograph, August 2011] 10 mg QD Contraindicated (TVR); 2.5 mg q24h - not recommended (BOC) Interactions between HCV & HIV Medications Additive toxicities: anemia: ribavirin, zidovudine, DAAs CNS: interferon, efavirenz Negative 2-way interactions can sometimes occur concentrations of HIV agents concentrations of HCV DAAs Interactions Between HCV and HIV PIs Summary of Healthy Volunteer Studies Impact on HIV PI Cmin ATVr DRVr FPVr BOC TVR LPVr ATVr Impact on HCV AUC DRVr BOC TVR FPVr Dosing recommendations: Boceprevir: coadministration with ritonavir-boosted PIs is not recommended Telaprevir: do not administer with DRVr, FPVr or LPVr; ongoing evaluation with ATVr LPVr [van Heeswijk et al. CROI 2011, #119. Hulskotte et al. CROI 2012, #771LB]

5 Interactions Between HCV DAA & NNRTIs Summary of Healthy Volunteer Studies Impact on NNRTI PK BOC TVR -4 EFV EFV ETV ETV RVP RVP AUC Cm in AUC Cm in AUC Cmin EFV Impact on HCV DAA PK ETV BOC AUC BOC Cmin Dosing recommendations: Efavirenz: avoid with BOC, use 1125 mg TID telaprevir Etravirine:? with BOC, OK with telaprevir Rilpivirine: OK with telaprevir RPV TVR AUC TVR Cmin [van Heeswijk et al. CROI 2011, #119. Garg et al. 6 th HCV PK Wksp 2011, #PK_13. Victrelis Monograph Hammond et al. IWCPHT 2012 O-15. Kakuda et al. IWCPHT 2012 O_18] No Clinically Significant Interaction with Raltegravir and Boceprevir or Telaprevir Mean Raltegravir PK +/- Boceprevir BOC exposures similar to historical controls [de Kanter et al. CROI 2012, #772LB. van Heeswijk et al. ICAAC 2011, #A1-1738a.] Mean Raltegravir PK +/- Telaprevir with TVR: RAL 78% Cmin, 26% Cmax, 31% AUC Mean Telaprevir PK +/- RAL Antiretroviral Therapy for Treatment- Naïve Individuals NRTI backbone Tenofovir-FTC Abacavir/3TC AZT/3TC (preferred for MTCT) Antiretroviral Treatment Options for Patients on Boceprevir or Telaprevir PIs Boceprevir Avoid with PIr Possible ATVr???? Telaprevir Avoid DRVr, FPVr, LPVr ATVr OK NNRTI Efavirenz PI Atazanavir/r Integrase Inhibitor Raltegravir CCR5 Inhibitor Maraviroc NNRTIs Avoid EFV Etravirine (?) No data Dose with EFV Etravirine OK Rilpivirine OK Rilpivirine* Nevirapine Darunavir/r Fosamprenavir/r Lopinavir/r *added Aug 16, 2011 DHHS Rating Preferred Added Dec 1, 2009 Added Jan 10, Alternative Acceptable InSTIs Maraviroc NRTIs Raltegravir OK No data potential / MVC; potential benefit on fibrosis? Tenofovir OK Avoid AZT (anemia) Pharmacokinetic Interaction Between Methadone and Telaprevir HCV-negative volunteers on stable methadone rec d telaprevir 750 mg q8h x 7 days Total R-Methadone AUC 29% and Cmin 31%, but unbound concentrations No withdrawal symptoms No methadone dosage adjustment necessary with telaprevir Van Heeswijk R, et al. EASL 2011, Berlin Germany, poster 1244 Managing Drug Interactions: 1) Medication Reconciliation Ensure medication records are up to date at each visit Rx, OTC, herbal/cam, recreational, etc. confirm doses, prn drugs include all agents that have been started or stopped Patient education Communication with other HCP!

6 Managing Drug Interactions: 2) Identify Potential Interactions Use a systematic approach to identify combinations of potential concern Apply knowledge of known PK characteristics overlapping CYP pathways, substrate, inducer, inhibitor High index of suspicion with key classes of drugs Drugs Contraindicated with Boceprevir and Telaprevir (1) α1-adrenoreceptor antagonist antiarrhythmics antimycobacterials Ergot derivatives Herbal product Statins neuroleptic alfuzosin Quinidine, propafenone, amiodarone. Flecainide (TVR) Rifampin St. John s wort Lovastatin, simvastatin. Atorvastatin (TVR) Pimozide [Victrelis & Incivek Product Monographs, 2011] hypotension, cardiac arrhythmia serious/life-threatening cardiac arrhythmia Loss of virologic response Acute ergot toxicity Loss of virologic response Myopathy including rhabdomyolysis serious/life-threatening cardiac arrhythmia Drugs Contraindicated with Boceprevir and Telaprevir (2) Cardiac: Statins, CCB, antiarrhythmics Ergots, PDE5 inhibitors PDE-5 inhibitor Sedatives/ hypnotics Other Anticonvulsants (BOC) OC (BOC) Aldosterone antagonist (TVR) Triptans (TVR) sildenafil. tadalafil (BOC); vardenafil (TVR) oral midazolam, triazolam cisapride, astemizole, terfenadine carbamazepine, phenytoin, phenobarbital drospirenone eplerenone eletriptan [Victrelis & Incivek Product Monographs, 2011] Visual abnormalities, hypotension, prolonged erection, syncope Increased sedation or respiratory depression serious/life-threatening cardiac arrhythmia Loss of virologic response hyperkalemia hyperkalemia Coronary artery vasospasm, MI, vent. tachycardia, VF Antiinfectives: Rifamycins, Azoles, Macrolides Psychotropics, sedatives Anticonvulsants Managing Drug Interactions: 3) Resources Consult pertinent interaction resources, pharmacology/pharmacy specialists not all combinations are listed in monographs new data often emerging use specialized resources when possible May need to extrapolate/infer from existing data

7 Managing Drug Interactions: 4) Management Determine if any drugs can be permanently or temporarily d/c while on DAA treatment Other options depend upon therapeutic range of drugs, available alternatives, and severity of co-morbid condition(s) Patient counselling & close monitoring is critical Summary High potential for pharmacokinetic interactions between directly acting antivirals and other drug classes Often, interactions can be managed, but heightened level of awareness is needed Many lessons learned from HIV can be applied Importance of a specialized, inter-disciplinary team including pharmacy