Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials Group (ACTG) 401

J Acquir Immune Defic Syndr. 2001 Jun 1;27(2):153-60. doi: 10.1097/00126334-200106010-00010.


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 antiretroviral 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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Drug Interactions
  • Female
  • HIV Infections / drug therapy
  • HIV Protease Inhibitors / administration & dosage*
  • HIV-1 / physiology
  • Humans
  • Male
  • Methadone / pharmacokinetics*
  • Methadone / therapeutic use
  • Middle Aged
  • Narcotics / pharmacokinetics*
  • Narcotics / therapeutic use
  • Ritonavir / administration & dosage*
  • Ritonavir / blood
  • Saquinavir / administration & dosage*
  • Saquinavir / blood
  • Stereoisomerism
  • Substance Abuse, Intravenous / complications
  • Substance Abuse, Intravenous / rehabilitation


  • HIV Protease Inhibitors
  • Narcotics
  • Saquinavir
  • Ritonavir
  • Methadone