Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with amprenavir in opioid-dependent subjects.
OBJECTIVE
To investigate the steady-state pharmacokinetics of methadone enantiomers when coadministered with amprenavir.


METHODS
Prospective, open-label, within-subject pharmacokinetic study.


METHODS
University research center.


METHODS
Nineteen opioid-dependent, methadone-maintained, healthy individuals were enrolled.


METHODS
On study day 1, subjects received their usual once-daily dose of methadone alone. On study days 2-11, they received the same once-daily methadone dose plus amprenavir 1200 mg twice/day. Serial blood samples were collected over 24 hours on study days 1 and 11 for measurement of plasma R- and S-methadone, and over 12 hours on day 11 for serum amprenavir concentrations.


RESULTS
Standard pharmacokinetic parameters were determined from the concentrations and compared between the two treatments (methadone alone vs methadone with amprenavir). Subjects served as their own control for methadone comparisons, and amprenavir comparisons were made by using a historic control group (38 healthy men). Opioid-effect measures were assessed throughout the study. Coadministration of amprenavir with methadone resulted in a 3-4-hour delay in plasma R- and S-methadone enantiomer peak concentrations at steady state (Cmax-ss). The active R-methadone enantiomer area under the plasma concentration-time curve during a dosing interval (AUCt-ss, Cmax-ss, and the minimum plasma concentration at steady state (Cmin-ss) were decreased by 13%, 25%, and 21%, respectively, after coadministration of methadone and amprenavir. The inactive S-enantiomer AUCt-ss, Cmax-ss, and Cmin-ss were decreased by 40%, 48%, and 52%, respectively. No clinically significant changes were noted in opioid pharmacodynamic effects, and there was no evidence of opioid withdrawal. No methadone dosage was changed in any subject.


CONCLUSIONS
No a priori adjustment in methadone dosage is required during coadministration with amprenavir as there is only a small effect on R-methadone exposure and no evidence of opioid withdrawal.
Johns Hopkins University School of Medicine, Baltimore, MD 21287-5554, USA. chendrix@jhmi.edu
Craig W
CW
Hendrix
John
J
Wakeford
Mary Beth
MB
Wire
Yu
Y
Lou
George E
GE
Bigelow
Elizabeth
E
Martinez
Jared
J
Christopher
Edward J
EJ
Fuchs
Jerry W
JW
Snidow
D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002219:Carbamates; D016001:Confidence Intervals; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005663:Furans; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D008297:Male; D008691:Methadone / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D009293:Opioid-Related Disorders / Q000534:rehabilitation*; D011930:Reaction Time / Q000187:drug effects; D013237:Stereoisomerism; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D019380:Anti-HIV Agents; D002219:Carbamates; D005663:Furans; D013449:Sulfonamides; C095108:amprenavir; D008691:Methadone