Drug-Drug Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned

Different views appear in the literature on the extent of specific cytochrome P450 (CYP) involvement in methadone metabolism. The aim of this work is to leverage knowledge from drug-drug interaction (DDI) studies in new drug applications between methadone and antiviral medications to better understand methadone disposition and to inform design of future DDI studies with methadone. A database of DDI studies between all FDA-approved human immunodeficiency virus and hepatitis C virus medications and methadone was constructed. The database contains data from 29 DDI studies. Sixteen of the 29 studies had statistically significant changes in methadone area under the concentration-time curve. Methadone exposure was either decreased or unchanged when it was coadministered with weak to strong CYP3A inhibitors or a moderate CYP3A4 inducer. Methadone exposure was reduced when it was coadministered with CYP2B6 inducers. The role of other enzymes (CYP2C9, CYP2C19, and CYP2D6) cannot be fully elucidated from these studies. In conclusion, CYP2B6 plays a prominent role in methadone metabolism, although methadone exposure is not sensitive to CYP3A perturbation. In designing methadone DDI studies, (1) measuring R- and S-methadone is more informative than measuring total methadone, and (2) CYP2B6 genotyping of subjects enrolled in methadone DDI studies should be considered. Finally, there is a need for the development of predictive models to determine the influence of medications on methadone disposition.