Effect of Steady-State Faldaprevir on the Pharmacokinetics of Steady-State Methadone and Buprenorphine-Naloxone in Subjects Receiving Stable Addiction Management Therapy

Abstract

eThe effects of steady-state faldaprevir on the safety, pharmacokinetics, and pharmacodynamics of steady-state methadone and buprenorphine-naloxone were assessed in 34 healthy male and female subjects receiving stable addiction management therapy. Subjects continued receiving a stable oral dose of either methadone (up to a maximum dose of 180 mg per day) or buprenorphine-naloxone (up to a maximum dose of 24 mg-6 mg per day) and also received oral faldaprevir (240 mg) once daily (QD) for 8 days following a 480-mg loading dose. Serial blood samples were taken for pharmacokinetic analysis. The pharmacodynamics of the opioid maintenance regimens were evaluated by the objective and subjective opioid withdrawal scales. Coadministration of faldaprevir with methadone or buprenorphine-naloxone resulted in geometric mean ratios for the steady-state area under the concentration-time curve from 0 to 24 h (AUC 0 -24,ss ), the steady-state maximum concentration of the drug in plasma (C max,ss ), and the steady-state concentration of the drug in plasma at 24 h (C 24,ss ) of 0.92 to 1.18 for (R)-methadone, (S)-methadone, buprenorphine, norbuprenorphine, and naloxone, with 90% confidence intervals including, or very close to including, 1.00 (no effect), suggesting a limited overall effect of faldaprevir. Although individual data showed moderate variability in the exposures between subjects and treatments, there was no evidence of symptoms of opiate overdose or withdrawal either during the coadministration of faldaprevir with methadone or buprenorphine-naloxone or after faldaprevir dosing was stopped. Similar faldaprevir exposures were observed in the methadone-and buprenorphine-naloxone-treated subjects. In conclusion, faldaprevir at 240 mg QD can be coadministered with methadone or buprenorphine-naloxone without dose adjustment, although given the relatively narrow therapeutic windows of these agents, monitoring for opiate overdose and withdrawal may still be appropriate. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637922.) I ntravenous drug abuse is currently the major source of hepatitis C virus (HCV) transmission in the United States (1, 2), with 53 to 96% of intravenous drug abusers testing positive for the anti-HCV antibody (3). In addition, approximately 67 to 96% of patients on opiate maintenance therapy, such as methadone or buprenorphine-naloxone (Suboxone), are also positive for the anti-HCV antibody (3). Faldaprevir (formerly called BI 201335) is a selective inhibitor of HCV NS3/4A protease, developed for the treatment of HCV genotype 1 infection in combination with pegylated interferon alpha 2a and ribavirin (4).Faldaprevir is metabolized primarily by cytochrome P450 3A4 (CYP3A4), and in vivo data suggest that 240 mg faldaprevir twice daily (BID) is a moderate inhibitor of CYP3A and a weak inhibitor of CYP2C9 (5). At the therapeutic dose of 120 mg once a day (QD), faldaprevir is a weak inhibitor of CYP3A and has no effect on CYP2C9 (6). Methadone hydrochloride is a synthetic opi...

Effect of Steady‐State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open‐Label, Fixed‐Sequence Crossover Study

“…Faldaprevir exposure was similar following coadministration of atorvastatin (faldaprevir AUC τ ,ss , 145 000 ng·h/mL) or rosuvastatin (faldaprevir AUC τ ,ss , 136 000 ng·h/mL). In addition, the exposure to faldaprevir observed in this study was comparable to that from historical data, 16 indicating that there was no meaningful effect of the statins on FDV exposure.…”

“…PK analyses for atorvastatin, ortho‐hydroxyatorvastatin, para‐hydroxyatorvastatin, rosuvastatin, N‐desmethylrosuvastatin, and FDV in plasma were conducted via the noncompartmental method using WinNonlin software, version 5.2 (Pharsight, Mountain View, California). The detailed analysis methods used have been described previously for single‐dose pharmacokinetics (atorvastatin and rosuvastatin and their respective metabolites) and steady‐state pharmacokinetics (FDV) . Summary statistics were reported for all parameters.…”

“…The detailed analysis methods used have been described previously for single-dose pharmacokinetics (atorvastatin and rosuvastatin and their respective metabolites) 15 and steady-state pharmacokinetics (FDV). 16 Summary statistics were reported for all parameters.…”

Pharmacokinetic Interaction between Faldaprevir and Cyclosporine or Tacrolimus in Healthy Volunteers: A Prospective, Open‐Label, Fixed‐Sequence, Crossover Study

“…Pharmacokinetic analyses of CsA, TAC and FDV concentrations were conducted using non‐compartmental methods in WinNonlin (Pharsight, Mountain View, CA, USA; version 5.2). The details of these methods have been described previously for single‐dose pharmacokinetics and steady‐state pharmacokinetics . Briefly, the area under the plasma concentration–time curve (AUC) was calculated using the trapezoidal rule, with the linear up/log down algorithm.…”