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The aim of this work is to leverage knowledge from drug\u2010drug 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\u2010approved 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\u2010time 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\u2010 and S\u2010methadone 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.<\/jats:p>","DOI":"10.1002\/jcph.1405","type":"journal-article","created":{"date-parts":[[2019,4,12]],"date-time":"2019-04-12T03:29:23Z","timestamp":1555039763000},"page":"1035-1043","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Drug\u2010Drug Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned"],"prefix":"10.1002","volume":"59","author":[{"given":"Islam R.","family":"Younis","sequence":"first","affiliation":[{"name":"Office of Clinical Pharmacology Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration  Silver Spring MD USA"},{"name":"Current affiliation: Astellas Pharma Global Development, Inc  Northbrook IL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth 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