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Limited Risk of Serious Interaction Between TMC278 and Methadone
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11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
Methadone levels fell moderately when this opiate replacement agent was taken with the investigational nonnucleoside TMC278 [1]. Tibotec investigators judged that the drops generally will not require dose adjustments if people on methadone maintenance therapy start TMC278, but they recommended monitoring these people for methadone withdrawal symptoms because some may require adjustments.
TMC278 has activity against virus resistant to other nonnucleosides, and it controlled HIV as well as efavirenz in a phase 2 trial that enrolled previously untreated people [2]. Two phase 3 trials of TMC278 at a dose of 25 mg once daily are under way in treatment-naive people. Because many HIV-infected injecting drug users receive methadone maintenance therapy, Tibotec investigators mounted this study to assess potential interactions between methadone and TMC278.
The trial involved 13 HIV-negative men on stable methadone maintenance. After 14 days of observation with participants taking methadone alone, the men added 25 mg of TMC278 once daily for 11 days. The investigators performed 24-hour sampling on the last day of methadone-only treatment and on the last day of methadone/TMC278 therapy. Methadone doses ranged from 60 to 150 mg daily and did change during the study.
Study volunteers had a median age of 41 years (range 31 to 54), a median weight of 84 kg (range 57 to 112), and a median body mass index of 26.4 kg/m(2) (range 20.3 to 33.4). Ten men were white, 2 were Asian, and 1 was black. One man did not comply with the trial protocol and dropped out of the study.
Methadone typically gets administered as a mixture of the R-isomer and the S-isomer of methadone. The R-isomer accounts for most of methadone's therapeutic effect. Adding TMC278 to methadone lowered the minimum concentration (Cmin), maximum concentration (Cmax), and 24-hour area under the curve (AUC) of both methadone isomers when compared with levels measured on methadone alone:
R-methadone
· Cmin 22% lower with TMC278
· Cmax 14% lower with TMC278
· 24-hour AUC 16% lower with TMC278
S-methadone
· Cmin 21% lower with TMC278
· Cmax 13% lower with TMC278
· 24-hour AUC 16% lower with TMC278
Methadone had no impact on levels of TMC278.
Nine of 12 volunteers experienced mild or moderate adverse events possibly or probably related to TMC278, and 4 had mild or moderate adverse events possibly related to methadone. There were no grade 3 or 4 adverse events, and no one dropped out because of adverse events. The investigators noted no rashes, no "notable variations" in ECGs, and no clinically relevant changes in lab values. No one had methadone withdrawal signs or symptoms.
Still, the Tibotec team cautioned that "clinical monitoring for methadone withdrawal symptoms is recommended [when starting TMC278] as methadone maintenance therapy may need to be adjusted in some patients."
References
1. Crauwels HM, van Heeswijk RPG, Vandevoorde A, et al. Pharmacokinetic interaction study between TMC278, a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), and methadone. 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Abstract 33.
2. Pozniak AL, Morales-Ramirez J, Katabira E, et al. Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial. AIDS. 2010;24:55-65. http://www.ncbi.nlm.nih.gov/pubmed/19926964
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