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

Summ.: The effect of ritonavir 400 mg/saquinavir 400 mg twice daily on the stereoselective pharmacokinetics of methadone was examined in 12 HIV-infect ed, 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 concen tration was measured by a chiral plasma assay because the drug is administe red as a racemic mixture of R- and S-methadone, but only the R-isomer is ac tive. Both changes in plasma protein binding and changes in objective and s ubjective opioid effect were monitored. Results: Ritonavir/saquinavir administration was associated with 40% decrea se in total S-methadone AUC(0-24h) and 32% decrease in R-methadone area und er the curve (AUC)(0-24hr), and both changes were statistically significant (p = .001 for both). When AUC was corrected for the changes in protein bind ing induced by ritonavir/saquinavir, R-methadone free AUC(0-24hr) decreased 19.6% whereas the S-methadone decreased 24.6%, neither of these changes wa s statistically significant (p = .129 and p = .0537, respectively). This ch ange in methadone exposure was not associated with any evidence of withdraw al 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 fo r the inactive S-methadone. However, approximately 37% of the decrease in t he total R-methadone exposure can be explained by protein binding displacem ent. Ritonavir/saquinavir can be used in HIV-infected people taking methado ne without routine dose adjustments.