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

Ying Jun Cao, Patrick F. Smith, Mary Beth Wire, Yu Lou, Charles T. Lancaster, Roger C. Causon, George E. Bigelow, Elizabeth Martinez, Edward J. Fuchs, Christine Radebaugh, Sarah McCabe, Craig W. Hendrix

Research output: Contribution to journalArticle

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 Main 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 (AUCT-SS) by 18%, maximum concentration at steady state (C max-ss) by 21%, and concentration at the end of the dosing interval at steady state (CT-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 AUCT-SS and Cmax-ss by 43% each, CT-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.

Original languageEnglish (US)
Pages (from-to)863-874
Number of pages12
JournalPharmacotherapy
Volume28
Issue number7
DOIs
StatePublished - Jul 1 2008

Keywords

  • Amprenavir
  • Fosamprenavir
  • Methadone
  • Pharmacodynamics
  • Pharmacokinetics
  • Ritonavir

ASJC Scopus subject areas

  • Pharmacology (medical)

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