Effect of ritonavir-boosted danoprevir, a potent hepatitis C virus protease inhibitor, on the pharmacokinetics of methadone in healthy subjects undergoing methadone maintenance therapy.
OBJECTIVE
To investigate the steady-state pharmacokinetics of methadone when coadministered with ritonavir-boosted danoprevir (DNVr).


METHODS
Open-label, two-period, single-sequence pharmacokinetic study.


METHODS
Two U.S. research centers.


METHODS
Eighteen methadone-maintained healthy adults.


RESULTS
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 AUCtau and Cmax 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.


CONCLUSIONS
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.
Hoffmann-La Roche Inc., Nutley, New Jersey, United Kingdom.
Sebastian A
SA
Moreira
Peter N
PN
Morcos
Mercidita T
MT
Navarro
Nuria
N
Bech
Patrick F
PF
Smith
Barbara J
BJ
Brennan
D000293:Adolescent; D000328:Adult; D000368:Aged; D003521:Cyclopropanes; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D006801:Humans; D054833:Isoindoles; D007769:Lactams / Q000008:administration & dosage / Q000493:pharmacokinetics*; D047029:Lactams, Macrocyclic; D008691:Methadone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D058850:Opiate Substitution Treatment / Q000379:methods*; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011480:Protease Inhibitors; D013449:Sulfonamides; C553752:danoprevir; D011392:Proline; D019438:Ritonavir; D008691:Methadone
HCV; methadone maintenance; pharmacokinetics; ritonavir-boosted danoprevir