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.

Effect of gender and age on the relative bioavailability of doravirine: results of a Phase I trial in healthy subjects.

BACKGROUND: Doravirine is a potent, once-daily, non-nucleoside reverse transcriptase inhibitor with a distinct resistance profile in Phase III development for the treatment of HIV-1. As doravirine may be administered to women and the elderly, we investigated the effect of gender and age in doravirine pharmacokinetics. METHODS: In this Phase I, open-label, single-period, parallel-group investigation, doravirine 100 mg was administered to 36 healthy subjects in three groups: elderly men (n=12, 65-80 years), elderly women (n=12, 65-80 years) and young women (n=12, 18-50 years). Data for young men (n=6, 18-50 years) from a previous study were included as a comparator. Doravirine plasma pharmacokinetics and safety were assessed. RESULTS: No clinically meaningful effect on pharmacokinetics was observed in association with gender or age. Gender effects were assessed using combined data from elderly and young men versus elderly and young women because the datasets met predefined pooling criteria. The geometric mean ratios (GMRs; women/men [90% CIs]) of doravirine AUC0-∞, Cmax and C24h were 1.20 (1.03, 1.40), 1.42 (1.23, 1.64) and 1.02 (0.84, 1.24), respectively. Age effects were assessed separately in men and women because the datasets did not meet pooling criteria. The AUC0-∞, Cmax, and C24h GMRs (elderly/young) were 0.85 (0.67, 1.10), 0.92 (0.73, 1.16), 0.81 (0.59, 1.11), respectively for men and 0.97 (0.79, 1.19), 1.18 (0.98, 1.42), 0.94 (0.72, 1.21), respectively, for women. Doravirine was well-tolerated throughout the trial. CONCLUSIONS: Neither gender nor age affects the bioavailability of single-dose doravirine 100 mg in healthy subjects, thus supporting administration of doravirine 100 mg in elderly and adult women without dose adjustment.