Pharmacokinetics and Pharmacodynamics of Methadone Enantiomers After Coadministration With Amprenavir in Opioid-Dependent Subjects

Craig W. Hendrix, M.D.; John Wakeford, Pharm.D.; Mary Beth Wire, Pharm.D.; Yu Lou, M.S.; George E. Bigelow, Ph.D.; Elizabeth Martinez, B.S.N.; Jared Christopher, R.N.; Edward J. Fuchs, PA-C; Jerry W. Snidow, Pharm.D.

Disclosures

Pharmacotherapy. 2004;24(9) 

In This Article

Abstract and Introduction

Study Objective. To investigate the steady-state pharmacokinetics of methadone enantiomers when coadministered with amprenavir.
Design. Prospective, open-label, within-subject pharmacokinetic study.
Setting. University research center.
Subjects. Nineteen opioid-dependent, methadone-maintained, healthy individuals were enrolled.
Intervention. 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.
Measurements and Main 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 (AUCτ-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 AUCτ-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.
Conclusion. 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.

Injection drug use is an important risk factor for infection with the human immunodeficiency virus (HIV). More than one third of all cases of acquired immunodeficiency syndrome in the United States were acquired through injection drug use.[1] Under current treatment guidelines, HIV-infected individuals who inject opioids are treated with methadone and combination antiretroviral regimens, which may include protease inhibitors.[2] Methadone, a synthetic narcotic analgesic, is the most commonly used maintenance pharmacotherapy for treating opioid dependence.

The physiologic effects of methadone, including analgesia and suppression of withdrawal symptoms, are attributed to the R-enantiomer, which has 8-50 times more potent analgesic activity than that of the S-enantiomer.[3] Also, the R-enantiomer has a greater mean plasma clearance (0.158 vs 0.129 L/min), mean volume of distribution (497 vs 289 L), and mean half-life (37 vs 29 hrs) than those of the S-enantiomer.[3] Methadone undergoes hepatic N-demethylation and cyclization by the cytochrome P450 (CYP) 3A4 isoenzyme to yield pyrrolidines and pyrroline, which are excreted in urine and bile.[4,5,6] Other isoenzymes, including CYP2C and possibly CYP2D6, CYP1A2, and CYP2B6, may also be involved in methadone metabolism.[4,5,6,7]

Amprenavir (Agenerase; GlaxoSmithKline, Research Triangle Park, NC) has demonstrated a good safety profile and efficacy and is approved for use in combination with other antiretroviral agents for treatment of individuals with HIV type 1 (HIV-1). Amprenavir is highly bound (~90%) to plasma proteins, predominantly to a1-acid glycoprotein (AAG), and to a lesser extent, to albumin.[8] Amprenavir, like the other HIV protease inhibitors, is metabolized primarily by CYP3A4 and inhibits CYP3A4 in vitro.[9] In clinical studies, amprenavir has been shown to increase plasma concentrations of CYP3A4 substrates including ketoconazole[10] and rifabutin,[11] suggesting that methadone clearance may be decreased by amprenavir, thus increasing methadone exposure.

Since long-term coadministration of amprenavir and methadone may be necessary in some patients, characterization of the effect of ampre-navir on steady-state methadone pharmacokinetics and opioid pharmacodynamic effects is important for the effective treatment of patients with HIV who receive methadone maintenance regimens in order to avoid opioid withdrawal or toxicity. Therefore, this study was conducted to compare steady-state plasma methadone enantiomer pharmacokinetics and pharmacodynamic effects when methadone was administered alone or in combination with amprenavir to opioid-dependent subjects. In addition, the effect of methadone on steady-state serum amprenavir pharmacokinetics was compared with that in a historic control group.

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