Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with fosamprenavir-ritonavir in opioid-dependent subjects.
Pharmacotherapy
; 28(7): 863-74, 2008 Jul.
Article
em En
| MEDLINE
| ID: mdl-18576901
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 MAINRESULTS:
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Organofosfatos
/
Sulfonamidas
/
Carbamatos
/
Pró-Fármacos
/
Ritonavir
/
Fármacos Anti-HIV
/
Metadona
/
Entorpecentes
Tipo de estudo:
Clinical_trials
Limite:
Adult
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Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article