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

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 AUC_0-24hr 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 AUC_0-24hr 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.