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Effect of Ritonavir‐Boosted Danoprevir, a Potent Hepatitis C Virus Protease Inhibitor, on the Pharmacokinetics of Methadone in Healthy Subjects Undergoing Methadone Maintenance Therapy
Author(s) -
Moreira Sebastian A.,
Morcos Peter N.,
Navarro Mercidita T.,
Bech Nuria,
Smith Patrick F.,
Brennan Barbara J.
Publication year - 2014
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/phar.1341
Subject(s) - methadone , pharmacokinetics , ritonavir , medicine , pharmacology , methadone maintenance , anesthesia , viral load , human immunodeficiency virus (hiv) , virology , antiretroviral therapy
Study Objective To investigate the steady‐state pharmacokinetics of methadone when coadministered with ritonavir‐boosted danoprevir ( DNV r). Design Open‐label, two‐period, single‐sequence pharmacokinetic study. Setting Two U . S . research centers. Patients Eighteen methadone‐maintained healthy adults. Measurements and Main Results In Period 1 (Day −1), subjects received their daily methadone maintenance therapy ( MMT ). In Period 2 (Days 1–10), subjects received MMT plus DNV r 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 DNV r. Methadone withdrawal was assessed using the S ubjective O piate W ithdrawal Scale. Compared with MMT alone, methadone AUC tau and C max GMR (90% CI ) following coadministration with DNV r 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 DNV r. No instances of methadone withdrawal were reported. MMT in combination with DNV r was well tolerated. Conclusion Coadministration of DNV r with MMT resulted in no significant pharmacokinetic interactions or signs of methadone withdrawal. No dosage adjustment is needed for MMT when coadministered with DNV r.