Evaluation of the Pharmacokinetic Interaction Between Doravirine and Methadone

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor indicated for the treatment of HIV type 1 infection. A subset of people living with HIV receives methadone for the treatment of opioid addiction. The current study (NCT02715700) was an open-label, multiple-dose, drug interaction study in participants on a methadone maintenance program to investigate potential drug-drug interactions between doravirine and methadone. Participants received a stable methadone maintenance dose of 20 to 180 mg once daily for 14 days prior to day 1 and remained on their maintenance dose over days 1 through 7. On days 2 through 6, an oral dose of doravirine 100 mg was coadministered. For doravirine and methadone pharmacokinetic analysis, blood samples were collected before dosing through 24 hours after dosing. Fourteen participants were enrolled; all participants completed the study. For R-methadone, geometric least squares mean ratios (90% confidence intervals) for dose-normalized area under the plasma concentration-time curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration ([methadone + doravirine]/methadone alone) were 0.95 (0.90-1.01), 0.95 (0.88-1.03), and 0.98 (0.93-1.03), respectively. For doravirine, based on a comparison with historical data, modest decreases in area under the plasma concentration-time curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration were observed after coadministration of doravirine and methadone; geometric least squares mean ratios ([methadone + doravirine]/doravirine alone [90% confidence intervals]) were 0.74 (0.61-0.90), 0.80 (0.63-1.03), and 0.76 (0.63-0.91), respectively. Coadministration of doravirine and methadone was generally well tolerated. No serious adverse events occurred, and there were no discontinuations. In conclusion, coadministration of methadone and doravirine did not have a clinically meaningful effect on the pharmacokinetic profile of either agent.