Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Current affiliation: Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
J Clin Pharmacol. 2019 Aug;59(8):1035-1043. doi: 10.1002/jcph.1405. Epub 2019 Apr 11.
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.
不同文献对特定细胞色素 P450（CYP）在美沙酮代谢中的参与程度有不同的观点。本研究旨在利用药物相互作用（DDI）研究中美沙酮与抗病毒药物之间的知识，更好地了解美沙酮的处置情况，并为未来美沙酮的 DDI 研究提供信息。构建了一个包含所有 FDA 批准的人类免疫缺陷病毒和丙型肝炎病毒药物与美沙酮之间 DDI 研究的数据库。该数据库包含来自 29 项 DDI 研究的数据。29 项研究中有 16 项研究显示美沙酮浓度-时间曲线下面积有统计学意义的变化。当美沙酮与弱至强 CYP3A 抑制剂或中度 CYP3A4 诱导剂合用时，美沙酮暴露量减少或不变。当与 CYP2B6 诱导剂合用时，美沙酮暴露量减少。这些研究不能充分阐明其他酶（CYP2C9、CYP2C19 和 CYP2D6）的作用。总之，CYP2B6 在美沙酮代谢中起着重要作用，尽管美沙酮暴露对 CYP3A 扰动不敏感。在设计美沙酮 DDI 研究时，（1）测量 R-和 S-美沙酮比测量总美沙酮更有意义，（2）应考虑对参加美沙酮 DDI 研究的受试者进行 CYP2B6 基因分型。最后，需要开发预测模型来确定药物对美沙酮处置的影响。
