SummaryThe 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.DesignA 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.ResultsRitonavir/saquinavir administration was associated with 40% decrease in total S-methadone AUC0–24hrand 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 AUC0–24hrdecreased 19.6% whereas the S-methadone decreased 24.6%, neither of these changes was statistically significant (p= .129 andp= .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.ConclusionsOur 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.