Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with fosamprenavir-ritonavir in opioid-dependent subjects.
OBJECTIVE
To compare steady-state pharmacokinetics and pharmacodynamics of methadone enantiomers when coadministered with fosamprenavir 700 mg-ritonavir 100 mg twice/day.


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


METHODS
Two university-affiliated research centers.


METHODS
Twenty-six opioid-dependent, methadone-maintained, healthy adults.


METHODS
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).


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.


CONCLUSIONS
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.
Cao
Ying-Jun
YJ
Division of Clinical Pharmacology, Johns Hopkins University, Baltimore, Maryland 21287-5554, USA.
Smith
Patrick F
PF
Wire
Mary Beth
MB
Lou
Yu
Y
Lancaster
Charles T
CT
Causon
Roger C
RC
Bigelow
George E
GE
Martinez
Elizabeth
E
Fuchs
Edward J
EJ
Radebaugh
Christine
C
McCabe
Sarah
S
Hendrix
Craig W
CW
D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D005663:Furans; D006801:Humans; D008297:Male; D008691:Methadone / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009294:Narcotics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010755:Organophosphates / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D013237:Stereoisomerism; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D019380:Anti-HIV Agents; D002219:Carbamates; D005663:Furans; D009294:Narcotics; D010755:Organophosphates; D011355:Prodrugs; D013449:Sulfonamides; C095108:amprenavir; D019438:Ritonavir; D008691:Methadone; C426859:fosamprenavir