Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: Results of aids clinical trials group (ACTG) 401

John G. Gerber, Susan Rosenkranz, Yoninah Segal, Judith Aberg, Ronald D'Amico, Donna Mildvan, Roy Gulick, Valery Hughes, Charles Flexner, Francesca Aweeka, Ann Hsu, Joseph Gal

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79 Scopus citations


The effect of ritonavir 400 mg/saquinavir 400 mg twice daily on the stereoselective pharmacokinetics of methadone was examined in 12 HIV-infected, methadone-using study subjects. Design: A 24-hour methadone pharmacokinetic study was performed before anti-retroviral therapy was begun and after 15 days of therapy. Methadone concentration was measured by a chiral plasma assay because the drug is administered as a racemic mixture of R- and S-methadone, but only the R-isomer is active. Both changes in plasma protein binding and changes in objective and subjective opioid effect were monitored. Results: Ritonavir/saquinavir administration was associated with 40% decrease in total S-methadone AUC0-24hr and 32% decrease in R-methadone area under the curve (AUC)0-24hr, and both changes were statistically significant (p = .001 for both). When AUC was corrected for the changes in protein binding induced by ritonavir/saquinavir, R-methadone free AUC0-24hr decreased 19.6% whereas the S-methadone decreased 24.6%, neither of these changes was statistically significant (p = .129 and p = .0537, respectively). This change in methadone exposure was not associated with any evidence of withdrawal from narcotics and no modification of methadone dose was required. Conclusions: Our data indicate that ritonavir/saquinavir administration is associated with induction of metabolism of methadone but this is greater for the inactive S-methadone. However, approximately 37% of the decrease in the total R-methadone exposure can be explained by protein binding displacement. Ritonavir/saquinavir can be used in HIV-infected people taking methadone without routine dose adjustments.

Original languageEnglish
Pages (from-to)153-160
Number of pages8
JournalJournal of Acquired Immune Deficiency Syndromes
Issue number2
StatePublished - 1 Jun 2001
Externally publishedYes


  • Drug-drug interaction
  • Methadone
  • Narcotic effect
  • Ritonavir/saquinavir
  • Stereoselective pharmacokinetics


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