Effect of Ritonavir/Saquinavir on Stereoselection Pharmacokinetics of Methadone: Results of AIDS Clinical Trials Group (ACTG) 401 [Gerber JG et al. JAIDS 2001; 27: 153]: The authors performed a pharmacokinetic study of the interaction of ritonavir 400 mg/saquinavir 400 mg twice daily and methadone in 12 HIV-infected methadone-using patients. The assay method used distinguished the racemic forms, since only the R-isomer of methadone is active. With adjustment for protein binding, the PI combination reduced the R-methadone AUC (0-24 hours) by 19.6%. This reduction was not associated with evidence of withdrawal. The authors concluded that RTV/SQV can be used in patients taking methadone without dose adjustment. Nevertheless, they also warn that some patients may experience narcotic withdrawal, due to high individual variations in this drug interaction.
Comment: The authors raise a few important issues in the discussion: First, they pose a question regarding the magnitude of decrease in methadone required to produce narcotic withdrawal symptoms. In this case, the average reduction in AUC was 19%, and no symptoms were encountered. The second question concerns the CYP isoenzyme involved in methadone metabolism. Standard teaching is that it is CYP 3A4, but if this were true, the impact of ritonavir should have been much more substantial. Their conclusion is that there are probably other cytochrome p450 enzyme systems involved in methadone metabolism. This impression is supported by the observation that indinavir, which is a pure CYP 3A4 inhibitor, has no effect on methadone pharmacokinetics, nor does rifabutin, which induces CYP 3A4. Another issue concerns the relative effects of PIs versus NNRTIs on methadone pharmacokinetics. The available data seems to indicate that PIs are relatively safe but that efavirenz and nevirapine commonly cause narcotic withdrawal symptoms when given concurrently with methadone.
posted 7/3/2001

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