Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with fosamprenavir-ritonavir in opioid-dependent subjects

Abstract

Study objective: To compare steady-state pharmacokinetics and pharmacodynamics of methadone enantiomers when coadministered with fosamprenavir 700 mg-ritonavir 100 mg twice/day.

Design: Open-label, single-sequence, two-period crossover, drug-interaction study.

Setting: Two university-affiliated research centers.

Subjects: Twenty-six opioid-dependent, methadone-maintained, healthy adults.

Intervention: Subjects received their usual daily dose of methadone alone for 4 days (period 1). Subjects then received the same daily dose of methadone plus fosamprenavir 700 mg-ritonavir 100 mg twice/day for 14 days (period 2).

Measurements and main results: Blood was collected on days 1-4 (period 1) and on days 11-14 (period 2) for plasma R- and S-methadone concentrations; amprenavir concentrations were assessed during period 2. Opioid-effect measures were assessed in each study period. Subjects served as their own controls for comparison of period 1 with period 2. Coadministration of fosamprenavir-ritonavir with methadone reduced plasma total R-methadone area under the plasma concentration-time curve over the dosing interval at steady state (AUC tau-ss) by 18%, maximum concentration at steady state (Cmax-ss) by 21%, and concentration at the end of the dosing interval at steady state (Ctau-ss) by 11%; time to reach Cmax-ss (Tmax) was delayed by 1.75 hours. Coadministration of fosamprenavir-ritonavir with methadone also reduced plasma total S-methadone AUC tau-ss and Cmax-ss by 43% each, Ctau-ss by 41%, and delayed Tmax by 0.85 hours. Fosamprenavir-ritonavir administered with methadone did not alter plasma amprenavir pharmacokinetics compared with historical control data; nor did it alter the unbound R-methadone at 2 and 6 hours after methadone dosing. Pharmacodynamic indexes remained essentially unchanged after adding fosamprenavir-ritonavir to methadone. No subject demonstrated opioid intoxication or withdrawal, or requested methadone dosage modification.

Conclusion: No adjustment in the dosages of either methadone or fosamprenavir 700 mg-ritonavir 100 mg twice/day is required during coadministration, on the basis of the small reduction in total R-methadone exposure, no change in unbound R-methadone, no clinically important opioid effects, and no change in amprenavir exposure.