Ritonavir Decreases Methadone Blood Levels in Healthy Volunteers

When taken together, methadone and protease inhibitors can have a drug interaction where there is a change in blood levels of one or both of the compounds. Methadone is processed through the same pathway in the liver as protease inhibitors and NNRTIs. Methadone is metabolized mainly by cytochrome P450 enzymes CYP3A, and by CYP2D6, 2C9 and 2C19 to a lesser degree. Ritonavir is a potent inhibitor of CYP3A. At ICAAC ‘97, it was reported from an in vitro study that methadone AUC would increase two fold when co-administered with ritonavir. Co-administration with indinavir should lead to a 30% increase in methadone AUC and the authors suggested a human study be conducted to validate the data.

Dr. Ann Hsu and others from Abbott Labs presented data from a study that was not done in test tubes, but in humans, at the Retrovirus Conference. Eleven healthy volunteers received a single 20mg dose of methadone orally on day one. During days 15-28, they received ritonavir, escalating the dose daily. On day 15, they were given 300 mg bid ritonavir, followed by 400 mg bid on day 16, and 500 mg bid on days 17-28. On day 25, they received a single dose of 5mg methadone.

In contrast to the previous study that was not conducted in humans, investigators reported decreases in dose-normalized methadone AUC, which is the drug blood level a over fixed period of time, and Cmax, which is the peak drug blood level. The changes were estimated to be a decrease of 36% and 38%, respectively. The terminal phase half-life for methadone was similar in the absence and presence of ritonavir. Ritonavir blood levels were comparable to historical data, suggesting methadone had no appreciable effect on ritonavir PK.

Investigators said this study demonstrates that in vitro, (in test tubes), data may not accurately predict in vivo (in humans) drug interactions. Investigators suggested that based on this study, a slight increase of the methadone dose in patients receiving ritonavir may be necessary. The ACTG is planning a separate study in individuals who are HIV infected who take methadone.