No Clinically Relevant Interaction between New NNRTI Etravirine (Intelence) and Methadone

As previously reported, the U.S. Food and Drug Administration (FDA) recently approved the second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (Intelence, formerly TMC125).

Whenever a new drug is introduced, it is important to determine its potential for interactions with other medications. Etravirine is an inducer of CYP3A, an enzyme that processes drugs in the liver, and an inhibitor of CYP2C. In the January 14, 2008 advance online Journal of Clinical Pharmacology, researchers from the University of Amsterdam and manufacturer Tibotec reported on a study of interactions between etravirine and methadone.

Methadone Tablet

Methadone is used as maintenance therapy by patients attempting to stop using heroin and other opiate drugs. An older NNRTI, nevirapine (Viramune), can speed up the processing of methadone, leading to low blood levels and opiate withdrawal symptoms.

The present open-label study evaluated the effect of etravirine on the pharmacokinetics and pharmacodynamics of methadone in 16 HIV negative male volunteers on stable methadone maintenance therapy. They received 100 mg etravirine twice daily (the approved standard dose) for 14 days.

Plasma concentrations and pharmacokinetic parameters of R- and S-methadone isomers (2 structural variations of the molecule) were determined one day before etravirine administration, then at days 7 and 14. Etravirine was measured on days 7 and 14. Safety and tolerability were also assessed.

Results

• The LSmeans ratio for the 24-hour area under the curve (AUC24h) of pharmacologically active R-methadone compared with methadone alone was 1.08 (90% CI 1.02-1.13) at day 7 and 1.06 (0.99-1.13) on day 14.

• LSmeans ratios for the maximum (Cmax) and minimum (Cmin) concentrations of pharmacologically active R-methadone compared with methadone alone were 1.03 (0.97-1.09) and 1.12 (1.05-1.19), respectively, on day 7, and 1.02 (0.96-1.09) and 1.10 (1.02-1.19) on day 14.

• No opiate withdrawal symptoms were observed and methadone dose adjustment was not required.

Conclusion

“The concomitant administration of [etravirine] and methadone was generally safe and well tolerated,” the authors concluded. “[Etravirine] has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of methadone. No dose adjustment for methadone is anticipated when coadministered with [etravirine].”

Tibotec BVBA, Tibotec Inc. & University of Amsterdam