Doravirine is a novel, potent, HIV-1 non-nucleoside reverse transcriptase inhibitor in development that is primarily metabolized by oxidation via CYP3A4. Ritonavir (RTV) is both an inhibitor of CYP3A and a general inducer of enzymes that may metabolize doravirine. The objective of this study was to assess the effect of multiple doses of RTV on the pharmacokinetics (PK) of doravirine.
This was an open-label, 2-period, fixed-sequence study in healthy adult subjects. In Period 1 (P1), a single dose of doravirine 50 mg was administered on Day 1. In Period 2 (P2), following a 7-day washout, RTV 100 mg was administered twice daily for 20 days and co-administered with doravirine 50 mg the morning of Day 14. Blood samples to measure doravirine concentrations were collected through 120 and 168 hours post doravirine dose in P1 and P2, respectively.
Eight adult male subjects were enrolled and completed the study. Following co-administration with multiple-doses of RTV, doravirine AUC, Cmax, and C24hr increased. The geometric mean (GM) ratios (90% confidence intervals) [(doravirine +RTV)/doravirine] for doravirine AUC0-∞, Cmax, and C24hr were 3.54 (3.04, 4.11), 1.31 (1.17, 1.46), and 2.91 (2.33, 3.62), respectively. The apparent GM (GCV%) half-life (hr) of doravirine was increased when co administered with RTV, 13.97 (10.59%) and 35.16 (12.27%), respectively. The median (range) Tmax (hr) values following a single dose of doravirine alone and when co administered with RTV were 3.50 (2.00, 5.00) and 5.00 (1.00, 16.00), respectively. Eight subjects reported a total of 22 adverse events (AEs); all AEs, with the exception of one headache of moderate intensity, were mild. There were no serious AEs and no discontinuations due to an AE.
Consistent with the metabolic profile of doravirine, co-administration of doravirine with the CYP3A inhibitor RTV significantly increased doravirine AUC0-∞ and C24hr, with a more modest increase in Cmax, via CYP3A inhibition. Doravirine was generally well tolerated when administered alone or with RTV.