Slide 1 Interaction profile of the new DAAs David Back University of Liverpool UK David Back University of Liverpool June 8th 2012
Why worry about Drug Drug Interactions (DDIs) in managing HCV patients? Current interactions (limited) involving pegylated interferon/ribavirin are well documented. However the DAAs have increased potential for DDIs An Interaction can alter the exposure of either the DAA or a co-medication Concern is i) loss of antiviral efficacy or toxicity and ii) loss of efficacy or toxicity of co-medication. DDI: drug drug interaction; HCV: hepatitis C virus
Drug Conc. Drug Conc. Enzyme inhibition and induction: effect of introducing another drug when steady state has already been reached Enzyme Inhibition Enzyme Induction Inhibiting Drug Inducing 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
Understanding the disposition of the currently licensed DAAs Drug Telaprevir Boceprevir Dosing regimen Q8h Taken with food (20 g of fat) 3 x daily Taken with food CYP metabolism CYP 3A4: Metabolised by Markedly Inhibits CYP 3A4: Metabolised by Markedly Inhibits Non-CYP metabolism AKR Metabolise d by P-gp Transporter Substrate Inhibitor Substrate AKR: aldo-keto reductase; DAA: direct-acting antiviral Q8h: every 8 hours; RTV: ritonavir; tid: three times daily Telaprevir EU SmPC; Boceprevir EU SmPC Kassera C, et al. CROI 2011. Abstract 118; Garg V, et al. CROI 2011. Abstract 629
Telaprevir and Boceprevir are metabolised by and inhibit CYP3A4 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 CYP: cytochrome P450 All percentages are approximate. For illustrative purposes, hepatic CYP enzymes present at <5% are all represented as 3.3% Proportion of drugs that are substrates for major CYP enzymes Hacker MP, et al. Pharmacology: Principles and Practice. Academic Press 2009
Drugs can be metabolised in the Gastrointestinal tract and Liver Small Intestines Liver CYP3A Pgp CYP3A P-gp: P-glycoprotein Adapted from Bailey DG, et al. Br J Clin Pharmacol. 1998:46:101 10
Telaprevir & Boceprevir increase exposure to CYP3A substrates: Perpetrator Drug TVR effect on the AUC (exposure) BOC effect on the AUC (exposure) Cyclosporine A 4.6-fold increase 2.7-fold increase Manageable Difficult to manage Tacrolimus 70-fold increase 17-fold increase Midazolam 3.4-fold increase (i.v) 9-fold increase (oral) CI 6.3-fold increase (oral) CI Atorvastatin 7.9-fold increase 2.3-fold increase CI 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 EU SmPC; Hulskotte EGJ et al HEPDart 2011; Abs 122 and Abs 123; Kessara C et al, CROI 2011, Abs 118; Boceprevir EU SmPC
Telaprevir & Boceprevir decrease exposure to other CYP-metabolised drugs: Perpetrator Co-medication Escitalopram (SSRI) Metabolised by CYP2C19 TVR effect AUC 35% BOC effect AUC 21% Mechanism: Not clearly determined Doses may need to be increased when combined with telaprevir; but dose adjustment not anticipated with boceprevir. van Heeswijk R, et al. IWCPHT 2010. Abstract 12; Telaprevir EU SmPC; Hulskotte EGJ et al HEP Dart 2011; Abs 121; Boceprevir EU SmPC.
Telaprevir & Boceprevir decrease exposure to other CYP-metabolised drugs: Perpetrator Oral Contraceptive Effect of TVR on OC AUC Ethinyl estradiol 28% Norethindrone 11% 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 Oral Contraceptive Effect of BOC on OC AUC Ethinyl estradiol 24% Drospirenone 99% Garg V, et al. IWCPHT 2011. Abstract PK_17Telaprevir EU SmPC; Kassera C et al CROI 2011; Abs 118; Boceprevir EU SmPC.
Enzyme inducing agents reduce telaprevir and boceprevir exposure: Victim Effect on telaprevir Effect on boceprevir Co-medication AUC AUC Efavirenz (600 mg qd) 26% 19% (Cmin 44%) Decrease in Telaprevir exposure substantially offset by increasing dose to 1125 mg q8h. The clinical outcome of the observed reduction of boceprevir concentrations has not been directly assessed Telaprevir EU SmPC; van Heeswijk R et al, CROI 2011; Abstract 119. Modified from Kassera C, et al. CROI 2011. Abstract 118 Boceprevir EU SmPC
Total C min of R- methadone (ng/ml) Telaprevir interaction with Methadone: a further complication: Median free fraction of R-methadone (%) Median unbound R- methadone C min (ng/ml) 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 15 260 210 13 13 160 110 60 146 91 11 9 7 7.92 9.98 11 9 7 10.63 10.45 10 Methadone Methadone + TVR 5 Methadone Methadone + TVR Protein Binding Displacement 5 Methadone Methadone + TVR van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1):S491
Telaprevir interaction with Buprenorphine 13 HCV negative subjects stable on buprenorphine/naloxone therapy TVR had only relatively minor effect on BUP exposure (Cmax decreased by 20%) or nor-bup exposure No subject experienced withdrawal symptoms Luo X et al; HEP DART 2011; Abs 132
DAA Clinical Pharmacology Targeted drug-drug interaction studies are done in the development programme and some postlicensing. Telaprevir and Boceprevir are perpetrators and victims of DDIs and this gives rise to a degree of nervousness Many DDIs can be explained on the basis of interaction with CYP3A4 but not all. DAA: direct-acting antiviral; DDI: drug-drug interaction
DAAs and Lipid Lowering Agents LSM ratio (90% CI), based on AUC Co-administered drug Dosage Atorvastatin 20 mg * Co-administered drug Telaprevir 7.9 (6.8 9.1) Drug CYP3A4 substrate CYP3A4 inhibitor Transporter substrate Atorvastatin X OATP1B1/2B1 Cerivastatin X OATP1B1 Lovastatin Simvastatin Pravastatin Rosuvastatin Fluvastatin Pitavastatin Gemfibrozil X X 2C9 OATP1B1/3, OATP1B1, OATP1B1/2B1 OATP1A2/1B3 Contraindication or Caution when co-administering telaprevir and statins with CYP3A4 mediated metabolism but Can you avoid using a statin during DAA treatment?
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16 DAAs and Lipid Lowering Agents
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Contraindications with telaprevir and boceprevir Class Agent Telaprevir 1 Boceprevir 2 Alpha-1 receptor antagonists Antiarrhythmics Alfuzosin CI No recommendation Amiodarone, bepridil, quinidine CI (CI with class Ia/III except IV lidocaine) Bepridil contraindicated. Caution with amiodarone/quinidine Anticonvulsants Carbamazepine, phenobarbital, phenytoin CI No data available: not recommended Antihistamines Astemizole, terfenadine CI No recommendation Antimalarials Lumefantrine, halofantrine No recommendation CI Antimycobacterials Rifampicin CI No data available: not recommended Antipsychotics Pimozide CI CI Benzodiazepines Oral midazolam, oral triazolam CI CI Digestive motility stimulants Ergot rye derivatives Cisapride CI No recommendation Dihydroergotamine, ergonovine, ergotamine, methylergonovine Herbal products St. John s wort (Hypericum perforatum) CI No recommendation CI CI HMG-CoA reductase inhibitors Atorvastatin, simvastatin, lovastatin CI No data available. Therapeutic monitoring recommended (atorvastatin, simvastatin) PDE5 inhibitors* Sildenafil, tadalafil CI No recommendation Tyrosine kinase inhibitors Not specified No recommendation CI Italic: removed/not available in all countries; *for pulmonary arterial hypertension 1. Telaprevir EU SmPC; 2. Boceprevir EU SmPC
Implications for Clinical Practice 12 weeks Telaprevir + PR Peg-IFN alfa + ribavirin Peg-IFN alfa + ribavirin* Weeks 0 4 12 24 36 48 PR lead-in BOC + PR 24, 32 or 44 weeks** PR: peginterferon (Peg-IFN) + ribavirin *PR must be continued up to Week 48 in patients with cirrhosis, prior partial and null responders and in treatment-naïve patients or prior relapsers without cirrhosis not achieving undetectable HCV RNA at Week 4 and 12 (but with HCV RNA <1000 IU/mL at these timepoints) **In patients receiving 32 weeks of boceprevir, PR alone must be continued up to Week 48 Telaprevir EU SmPC; Boceprevir EU SmPC
HIV-HCV Co-Infection
Interaction of Telaprevir with Boosted HIV PIs (Healthy volunteer data) Change in AUC (%) Co-administered drug Lopinavir/r (LPV/r) Atazanavir/r (ATV/r) Darunavir/r (DRV/r) Fosamprenavir/r (fapv/r) n HIV PI Telaprevir 21 54% 20 17%* 20% 20 40% 35% 20 43% 32% LPV/r, DRV/r and fapv/r not recommended in combination with telaprevir * Cmin increased by ~ 70% Mechanistic understanding of observed DDI is inconsistent with CYP3A4 interactions q8h: every 8 hours Van Heeswijk R et al CROI 2011; Abs 119; Telaprevir EU SmPC
Interaction of Boceprevir and Boosted HIV PIs (Healthy volunteer data) Atazanavir/r Lopinavir/r Darunavir/r % Change in AUC of Boosted PI 35% 34% 44% % Change in AUC of Boceprevir 45% 32% Not recommended to coadminister boceprevir and ritonavir boosted PIs (FDA; Merck) ATV/r can be considered on a case by case basis if patient has no prior HIV drug resistance (EMEA) Hulskotte E et al; CROI 2012 Abs 771LB
Telaprevir & Boceprevir interaction with NNRTIs: NNRTI Effect of TVR on AUC Effect of NNRTI on TVR AUC Etravirine 16% Rilpivirine 1.8-fold 8% Based on the PK data - dose adjustment not considered necessary NNRTI Effect of BOC on AUC Effect of NNRTI on BOC AUC Etravirine 23% 10% Rilpivirine ND ND Based on the PK data - dose adjustment not required. Kakuda T et al; IWCPHT 2012; Abs 0_18; Hammond K et al, IWCPHT 2012; Abs 0-15
Telaprevir: Summary of DDIs with HIV antiretrovirals HIV antiretroviral Studies completed Atazanavir/r Darunavir/r Fosamprenavir/r Lopinavir/r Recommendation Clinical and laboratory monitoring for hyperbilirubinemia is recommended Not recommended Efavirenz Etravirine Rilpivirine Raltegravir (non CYP) Tenofovir TVR dose increase necessary (1125 mg q8h) No dose adjustment required* No dose adjustment required* No dose adjustment required** Increase in TFV (30%). Clinical and laboratory monitoring is warranted All the PK Interaction studies are in HEALTHY VOLUNTEERS * Data presented by Kakuda et al at 13 th HIV Pharmacology Workshop, Barcelona, April 16-18 th 2012; ** van Heeswijk R et al; ICAAC 2011; Abs A1-1738a Telaprevir EU SmPC
Telaprevir in Combination with Pegylated Interferon- -2a+RBV in HCV/HIV-co-infected Patients: A 24-Week Treatment Interim Analysis Douglas Dieterich* 1, V Soriano 2, K Sherman 3, P-M Girard 4, J Rockstroh 5, B Adiwijaya 6, S McCallister 6, N Adda 6, L Mahnke 6, M Sulkowski 7, on behalf of the Study 110 Team 1 Mt Sinai Sch of Med, New York, US; 2 Hosp Carlos III, Madrid, Spain; 3 Univ of Cincinnati, OH, US; 4 Hosp St Antoine, Paris, France; 5 Univ of Bonn, Germany; 6 Vertex Pharm Inc, Cambridge, MA, US; 7 Johns Hopkins Univ Sch Med, Baltimore, MD, US ATV/r did not cause a decrease in TVR concentrations (cf healthy) TVR dose increase compensated for EFV effect ATV concentrations increased in T + P/R group by 18% in keeping with healthy data. 25
Boceprevir: Summary of DDIs with HIV antiretrovirals HIV antiretroviral Studies completed Atazanavir/r Darunavir/r Lopinavir/r Not recommended Recommendation Efavirenz Etravirine Raltegravir (non CYP) Tenofovir Reduction in boceprevir levels; clinical outcome not directly assessed No dose adjustment required* No dose adjustment required** No change in TFV AUC but Cmax increased by 32%. No dose adjustment but clinical/laboratory monitoring warranted All the PK Interaction studies are in HEALTHY VOLUNTEERS *De Kanter C, et al. CROI 2012. Abstract 772LB; **Hammond K et al, IWCPHT 2012; Abs O-15 Abs Victrlelis SmPC
Boceprevir plus Peginterferon /Ribavirin for the Treatment of HCV/HIVco-infected Patients: End of Treatment (Week-48) Interim Results J Mallolas, S Pol, A Rivero, H Fainboim, C Cooper, J Slim, S Thomson, J Wahl, W Geaves, M Sulkowski, Spain, France, Argentina, Canada, USA. Percent with Virologic Response Included patients on ATV/r; LPV/r, DRV/r, Raltegravir. 100 P/R BOC + P/R 80 73,4 65,6 59,4 60,7 60 42,2 40 32,4 29,4 23,5 26,5 20 14,7 8,8 4,7 0 4 8 12 24 EOT SVR12 Treatment Week 27 EASL 2012; Abs 50
Boceprevir plus Peginterferon /Ribavirin for the Treatment of HCV/HIVco-infected Patients: End of Treatment (Week-48) Interim Results J Mallolas, S Pol, A Rivero, H Fainboim, C Cooper, J Slim, S Thomson, J Wahl, W Geaves, M Sulkowski, Spain, France, Argentina, Canada, USA. Included patients on ATV/r; LPV/r, DRV/r, Raltegravir. 3/64 pts on BOC + P/R had HIV breakthrough not suggestive of systematic interaction. SVR12 by HIV Drug PR (27%) BOC + PR (62.5%) ATV/r 8/13 (62%) 12/18 (67%) LPV/r 0/10 (0%) 10/15 (67%) DRV/r 0/5 (0%) 8/12 (67%) Other PI/r 0/3 (0%) 4/7 (57%) Raltegravir 1/3 (33%) 3/7 (43%) 28 EASL 2012; Abs 50
DAA Clinical Pharmacology The HCV-HIV interactions (Healthy volunteers) are: unexpected, inconsistent and difficult to explain. Need information on pharmacokinetics in HCV patients the magnitude of interactions maybe different. Interferon may be exerting enough anti HIV activity to protect against low HIV drug concentration. Perhaps total concentrations reduced but free concentrations less affected need data! We do have safer ARV options until there is clarity.
What about the next generation of DAAs?
TMC435 (Simeprivir) Reversible NS3/4A protease inhibitor 150 mg dose in Phase III Weak inhibitory effect on CYP3A suggest less DDI potential Methadone No effect of TMC435 on either R- or S-methadone in subjects stable on methadone therapy. Escitalopram No effect of TMC435 on escitalopram exposure Simmen K et al Int Liver Congress Hong Kong 2008; Abs 507. Beumont-Mauviel M et al AASLD 2011; Abs 1353 & 1354
TMC435 (Simeprivir) Interactions Efavirenz TMC435 AUC reduced by 71%. AVOID use. Rilpivirine No effect of RPV on TMC435 AUC. RPV exposure increased by 12%. No Dose Adjustment. Raltegravir TMC435 AUC decreased 11%. RPV exposure not altered. No Dose Adjustment. Tenofovir TMC435 AUC decreased 14%. TFV exposure increased 18%. No Dose Adjustment. Ouwerkerk-Mahadevan S et al 19 th CROI 2012; Abs 49
And... CYP3A substrate? Interaction Potential Interaction data BI 201355 YES Yes Awaited Daclatasvir YES Yes ATV/r increases DCV EFV decreases DCV TDF no effect on DCV Alisporivir YES Yes Awaited Danoprevir/r YES Boosted by ritonavir - Yes GS-7977 NO Intracellular phosphorylation -Less Awaited No effect on methadone 33 Sane R et al, 46 th EASL 2011; Bifano M et al; CROI 2012; Abs 618; Crabbe R et al; Exp Opin Inv Drugs 2009; 18: 211-220; Denning JM et al AASLD 2011; Abs 372.
34 Thank you