Drug-Drug Interactions

Drug-Drug Interactions David Back University of Liverpool UK David Back University of Liverpool C-Hep Berlin October 2012

Interactions with the new HepC drugs are challenging! Slide 2 Number of known interactions Number of potential interactions (based on metabolic profile) Magnitude of the interactions Applying data from Healthy Volunteer studies to HCV patients

What can we learn from other therapeutic areas: HIV? Slide 3 Most DDIs are manageable or avoidable - if recognised DDIs may be: - Anticipated - Unanticipated, but explainable - Unanticipated and inexplicable Most potential interactions remain unstudied PK effect clinically significant effect - Therapeutic window

The importance of the Therapeutic Window Slide 4 Conc Conc Toxicity Toxicity 2 fold 2 fold X 30% X 30% Compromise Efficacy Compromise Efficacy Narrow Therapeutic Window Wide Therapeutic Window

Key Mechanisms of Drug Interactions: Alteration of steady state of a drug in the regimen Enzyme Inhibition or Interaction with transporter Slide 5 Interacting Drug 1 2 3 4 5 6 7 8 9 10 11 12 Days

Key Mechanisms of Drug Interactions: Alteration of steady state of a drug in the regimen Enzyme Inhibition or Interaction with transporter Enzyme Induction or Interaction with transporter or Binding displacement Slide 6 Interacting Drug Interacting Drug 1 2 3 4 5 6 7 8 9 10 11 12 Days 1 2 3 4 5 6 7 8 9 10 11 12 Days

Telaprevir and Boceprevir are metabolised by and strongly inhibit CYP3A4 Slide 7 CYP 3A isozymes are the most abundant in the liver CYP 3A isozymes involved in the metabolism of majority of drugs CYP 1A2 CYP 2A6 CYP 2B6 CYP 2C8 CYP 2C9 CYP 2C8 CYP 2B6 CYP 2C9 CYP 2A6 CYP 1A2 CYP 2C19 CYP 2D6 CYP 3A CYP 2C19 CYP 2D6 CYP 3A CYP 2E1 CYP 2E1 Proportion of total CYP enzymes present in human liver Proportion of drugs that are substrates for major CYP enzymes Boceprevir also metabolised by Aldo-Keto Reductase (AKR) CYP: cytochrome P450 Hacker MP, et al. Pharmacology: Principles and All percentages are approximate. For illustrative purposes, Practice. Academic Press 2009 hepatic CYP enzymes present at <5% are all represented as 3.3%

Telaprevir & Boceprevir increase exposure to CYP3A substrates: Perpetrator Slide 8 Drug TVR effect on the AUC (exposure) BOC effect on the AUC (exposure) Cyclosporine A 4.6-fold increase 2.7-fold increase Manageable Tacrolimus 70-fold More increase challenging to 17-fold manage increase Midazolam 3.4-fold increase (i.v) 9-fold increase (oral) CI CI 6.3-fold increase (oral) Atorvastatin 7.9-fold increase 2.3-fold increase Amlodipine 2.79-fold? CI Dose reduce Dose reduce Dose reduce? Garg V, et al. Heptatology 2011:54:20 27; Garg V, et al. J Clin Pharmacol 2012 ; Lee JE, et al. Antimicrob Agents Chemother 2011;55:4569 74; Telaprevir SmPC; Hulskotte EGJ et al HEPDart 2011; Abs 122 and Abs 123; Kessara C et al, CROI 2011, Abs 118; Boceprevir SmPC

Changes in immunosuppression during the first 12 weeks of TVR-based therapy Slide 9 Immunosuppression Patients (N) Daily dose at baseline mg ± SD Av daily dose during triple therapy mg ± SD Av daily dose reduction Tacrolimus 4 1.125 ± 0.54 0.05 ± 0.04 22 (5-33.6) Sirolimus 1 0.5 0.07 7 Cyclosporin 4 122.5 ± 33.4 48.5 ± 19.0 2.5 (2-3.8) Werner CR et al Liver Transplantation 2012 (Epub ahead of print)

In the absence of specific DDI data we need to understand the metabolic profiles of drugs in the regimen in order to determine the potential for interaction

Interaction of Lipid Lowering Agents with TVR & BOC Slide 11 Drug Major Clearance Pathway Effect of TVR Effect of BOC Atorvastatin CYP3A4, OATP1B1 D D Lovastatin CYP3A4 Simvastatin CYP3A4 Pravastatin OATP1B1/3 D Rosuvastatin CYP2C9 (minor); OATP1B1 Fluvastatin CYPs(Multiple); OATP1B1/ 2B1 Pitavastatin (US) CYP2C9 (minor) UGT1A3; OATP1A2/1B3 Gemfibrozil D = Data from study Enzymes unknown From www.hep-druginteractions.org or individual SPCs

Interaction of Lipid Lowering Agents with TVR & BOC Drug Major Clearance Pathway Effect of TVR Effect of BOC Slide 12 Atorvastatin CYP3A4, OATP1B1 D D Lovastatin CYP3A4 Simvastatin CYP3A4 Pravastatin OATP1B1/3 D Rosuvastatin CYP2C9 (minor); OATP1B1 Fluvastatin CYPs(Multiple); OATP1B1/ 2B1 Pitavastatin (US) CYP2C9 (minor) UGT1A3; OATP1A2/1B3 Gemfibrozil D = Data from study Enzymes unknown Contraindication or Caution when co-administering statins with CYP3A4 mediated metabolism but can you avoid using a statin during DAA treatment? From www.hep-druginteractions.org or individual SPCs

If clearance involves just CYP3A4 co-med levels will increase. But if other additional metabolic pathways co-med levels could decrease. Also note other interaction mechanisms.

Telaprevir & Boceprevir decrease exposure of other CYP-metabolised drugs: Perpetrator Slide 14 TVR effect BOC effect Co-medication Escitalopram (SSRI) Metabolised by CYP2C19 & CYP3A4 AUC AUC 35% 21% Mechanism: Not clearly determined but INDUCTION of CYP2C19? Doses may need to be increased when combined with telaprevir Dose adjustment not anticipated with boceprevir. van Heeswijk R, et al. IWCPHT 2010. Abstract 12; Telaprevir SmPC; Hulskotte EGJ et al HEP Dart 2011; Abs 121; Boceprevir SmPC.

Other antidepressants that have not been studied with telaprevir Slide 15 Antidepressants metabolized by CYP 3A4 Antidepressants metabolized primarily by non CYP 3A4 http://www.hep-druginteractions.org

HIV-HCV co-infection Slide 16

Telaprevir & Boceprevir decrease exposure of HIV protease inhibitors Perpetrator Slide 17 Boosted PI % Change in AUC of Boosted PI by BOC % Change in AUC of Boosted PI by TVR Atazanavir/r 35% 17% Lopinavir/r 34% Darunavir/r 44% 32% Mechanism? CYP3A4 is inhibited by ritonavir; induction of another pathway Displacement from protein binding and increased clearance Van Heeswijk R et al CROI 2011; Abs 119; Telaprevir SmPC Hulskotte E et al; CROI 2012 Abs 771LB

Telaprevir and boceprevir are also Victims of drug interactions: HIV drugs Slide 18 Effect on Boceprevir Effect on Telaprevir Co-medication AUC AUC Efavirenz (600 mg qd) 19% (Cmin 44%) 26% Atazanavir/r 20% Darunavir/r 32% 35% Lopinavir/r 45% 54% Telaprevir SmPC; van Heeswijk R et al, CROI 2011; Abstract 119. Modified from Kassera C, et al. CROI 2011. Abstract 118 Boceprevir SmPC

But what if the HCV PI and HIV PI interaction was similar to TVR-Methadone?: During telaprevir co-administration vs methadone alone: Total C min of R-methadone reduced by 31% Free fraction of R-methadone increased by 26% No change in the unbound (effective) concentration of R-methadone 15 Total C min of R- methadone (ng/ml) 260 210 160 110 60 10 146 91 Methadone Methadone + TVR Median free fraction of R-methadone (%) 13 11 9 7 5 7.92 9.98 Methadone Methadone + TVR Median unbound R- methadone C min (ng/ml) Protein Binding Displacement 13 11 9 7 5 10.63 10.45 Methadone Methadone + TVR van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1):S491

So... Although total concentrations are reduced the free concentrations may be less affected need more data! AND... Is the magnitude of the interaction different in HCV patients?

Most DDI studies are in Healthy Subjects: Physiological Changes (vs. healthy volunteers) Parameter HCV-infected Albumin * 1 α1-acid glycoprotein 3 Gastric ph 4 Cytokines 6 Cytochrome P450 s 5 * Magnitude of effect dependent on stage of liver involvement Also hemodynamic changes with hepatic impairment Slide 21 1 Nagao Y & Sata M. Virology Journal 2010; 7: 375; 2 Monga HK et al. Clin Infect Dis 2001; 33: 240-7; 3 Ozeki T et al. Br J Exp Path 1988; 69: 589-95; 4 Nam YJ et al. Korean J Hepatol 2004; 10: 216-22; 5 Frye RF et al. Clinical Pharmacol Ther 2006; 80: 235-45; 6 Huang et al Clin Pharmacol Ther 2010; 87: 32-36

Differences in CYP enzymes in patients with hepatic impairment Chlorzoxazone 100 CYP3A4 Caffeine Debrisoquine % of control 80 60 40 20 Mephenytoin 0 CP-A (6) CP-B (21) CP-C (21)* Model of hepatic dysfunction and implications for clearance of drugs predominantly metabolized by CYP pathway in liver. Study in healthy volunteers and patients with liver disease Frye RF et al. Clinical Pharmacol Ther 2006; 80: 235-45 Johnson TN et al. Clinical Pharmacokin 2010; 49: 189-206

Patient 1. On darunavir/r 800/100 mg QD monotherapy Liver cirrhosis (liver stiffness 34kPa) DRV concentration at wk 5 of HCV therapy with BOC 3777 ng/ml (normal range) Patient 2. On fos-amprenavir/r 700/100 mg BID containing regimen Liver cirrhosis (liver stiffness 32kPa) FPV concentration at wk 8 of HCV therapy with BOC 1699 ng/ml (normal range)

Contraception Slide 24

Telaprevir & Boceprevir alter exposure of contraceptive steroids Additional methods of non-hormonal contraception should be used; ie hormonal contraceptives may be continued but may not be reliable during and immediately following TVR dosing. During this time, female patients of childbearing potential should use two effective non-hormonal methods of contraception. Potential compromised contraceptive efficacy Caution should be exercised in patients predisposed to hyperkalaemia. Garg V, et al. IWCPHT 2011. Abstract PK_17Telaprevir EU SmPC; Kassera C et al CROI 2011; Abs 118; Boceprevir EU SmPC.

What about the Mirena IUD and TVR? Slide 26 The metabolism of progestogens may be increased by concomitant use of substances known to induce drugmetabolising enzymes, specifically cytochrome P450 enzymes, such as anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz) 1. The influence of these drugs on the contraceptive efficacy of Mirena is not known, but it is not believed to be of major importance due to the local mechanism of action 1. www.mirena.com; www.medicines.org.uk

DDI management: a stepwise approach Be vigilant for DDIs when starting PI-based therapy Check all patient s concomitant drugs (prescribed/otc) and herbal products Consult the SmPCs of PIs Consult on-line resources and a pharmacist/ pharmacologist to seek guidance Slide 27

What about the second generation of drugs?

Drug Interactions with Simeprevir (TMC435) Drug Effect of TMC435 Effect of Drug on TMC435 Methadone (CYP3A4 & CYP2B6) Escitalopram (CYP2C19) Efavirenz (CYP2B6) Rilpivirine (CYP3A4) Raltegravir (UGTs) No effect na No effect na na 70% 12% No effect No effect 11% Na = not assessed Overall weaker inhibitory effect on CYP enzymes Simmen K et al Int Liver Congress Hong Kong 2008; Abs 507. Beumont-Mauviel M et al AASLD 2011; Abs 1353 & 1354

Drug Interactions with Faldaprevir (BI201355) Drug Oral Midazolam (CYP3A4) Omeprazole (CYP2C19) Efavirenz (CYP2B6) S-Warfarin (CYP2C9) Effect of BI201335 AUC GMR 2.92 1.58 1.16 1.29 Study in healthy volunteers (n=14-24); 240 mg BID BI201335. Sabo JP et al ICAAC 2012 Abs A-1248

Thank you! Slide 32