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

Craig Hendrix, John Wakeford, Mary Beth Wire, Yu Lou, George Bigelow, Elizabeth Martinez, Jared Christopher, Edward Fuchs, Jerry W. Snidow

Research output: Contribution to journalArticle

Abstract

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 (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 C min-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.

Original languageEnglish (US)
Pages (from-to)1110-1121
Number of pages12
JournalPharmacotherapy
Volume24
Issue number9
DOIs
StatePublished - Sep 4 2004

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Methadone
Opioid Analgesics
Pharmacokinetics
amprenavir

Keywords

  • Amprenavir
  • Enantiomers
  • Human immunodeficiency virus
  • Methadone
  • Opioid dependence
  • Pharmacodynamics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with amprenavir in opioid-dependent subjects. / Hendrix, Craig; Wakeford, John; Wire, Mary Beth; Lou, Yu; Bigelow, George; Martinez, Elizabeth; Christopher, Jared; Fuchs, Edward; Snidow, Jerry W.

In: Pharmacotherapy, Vol. 24, No. 9, 04.09.2004, p. 1110-1121.

Research output: Contribution to journalArticle

Hendrix, Craig ; Wakeford, John ; Wire, Mary Beth ; Lou, Yu ; Bigelow, George ; Martinez, Elizabeth ; Christopher, Jared ; Fuchs, Edward ; Snidow, Jerry W. / Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with amprenavir in opioid-dependent subjects. In: Pharmacotherapy. 2004 ; Vol. 24, No. 9. pp. 1110-1121.
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abstract = "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 (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 C min-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.",
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AU - Wakeford, John

AU - Wire, Mary Beth

AU - Lou, Yu

AU - Bigelow, George

AU - Martinez, Elizabeth

AU - Christopher, Jared

AU - Fuchs, Edward

AU - Snidow, Jerry W.

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N2 - 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 (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 C min-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.

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