Effect of Ritonavir‐Boosted Danoprevir, a Potent Hepatitis C Virus Protease Inhibitor, on the Pharmacokinetics of Methadone in Healthy Subjects Undergoing Methadone Maintenance Therapy. Issue 3 (14th August 2013)

• Record Type: Journal Article
• Authors: Moreira, Sebastian A.; Morcos, Peter N.; Navarro, Mercidita T.; Bech, Nuria; Smith, Patrick F.; Brennan, Barbara J.
• Is Part Of: Pharmacotherapy. Volume 34:Issue 3(2014)
• Page Start: 220
• Page End: 226
• Publication Date: 2013-08-14
• Subjects: Chemotherapy -- Periodicals; Pharmacology -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1002/phar.1341
• Languages: English
• ISSNs: 0277-0008

Abstract

<abstract abstract-type="main" id="phar1341-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="phar1341-sec-0001" sec-type="section"> <title>Study Objective</title> <p>To investigate the steady‐state pharmacokinetics of methadone when coadministered with ritonavir‐boosted danoprevir (DNVr).</p> </sec> <sec id="phar1341-sec-0002" sec-type="section"> <title>Design</title> <p>Open‐label, two‐period, single‐sequence pharmacokinetic study.</p> </sec> <sec id="phar1341-sec-0003" sec-type="section"> <title>Setting</title> <p>Two U.S. research centers.</p> </sec> <sec id="phar1341-sec-0004" sec-type="section"> <title>Patients</title> <p>Eighteen methadone‐maintained healthy adults.</p> </sec> <sec id="phar1341-sec-0005" sec-type="section"> <title>Measurements and Main Results</title> <p>In Period 1 (Day −1), subjects received their daily methadone maintenance therapy (MMT). In Period 2 (Days 1–10), subjects received MMT plus DNVr 100/100 mg twice/day. Pharmacokinetic parameters for the total concentrations of (R)‐ and (S)‐methadone on Days −1 and 10 were determined using noncompartmental methods. Unbound (R)‐ and (S)‐methadone concentrations at 3 hours postdose were also assessed on Days −1 and 10. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare steady‐state (R)‐ and (S)‐methadone pharmacokinetics when MMT was administered with or without DNVr. Methadone withdrawal was assessed using the Subjective Opiate Withdrawal Scale. Compared with MMT alone, methadone AUC<sub>tau</sub> and C<sub>max</sub> GMR (90% CI) following coadministration with DNVr were 1.02 (0.91–1.15) and 1.01 (0.90–1.13) for (R)‐methadone, and 1.01 (0.90–1.13) and 0.99 (0.89–1.10) for (S)‐methadone, respectively. Unbound (R‐ and (S)‐methadone concentrations were comparable with or without DNVr. No instances of methadone withdrawal were reported. MMT in combination with DNVr was well tolerated.</p> </sec> <sec id="phar1341-sec-0006" sec-type="section"> <title>Conclusion</title> <p>Coadministration of DNVr with MMT resulted in no significant pharmacokinetic interactions or signs of methadone withdrawal. No dosage adjustment is needed for MMT when coadministered with DNVr.</p> </sec> </abstract>