Doravirine is a novel non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1). A population pharmacokinetic (PK) model was developed for doravirine using pooled data from densely sampled Phase 1 trials and from sparsely sampled Phase 2b and Phase 3 trials evaluating doravirine administered orally as a single entity or as part of a fixed-dose combination of doravirine/lamivudine/tenofovir disoproxil fumarate. A one-compartment model with linear clearance from the central compartment adequately described the clinical PK of doravirine. While weight, age, and healthy versus HIV-1 status were identified as statistically significant covariates affecting doravirine PK, the magnitude of their effects was not clinically meaningful. Other intrinsic factors (gender, body mass index, race, ethnicity, and renal function) did not have statistically significant or clinically meaningful effects on doravirine PK. Individual exposure estimates for individuals in the Phase 2b and 3 trials obtained from the final model were used for subsequent exposure–response analyses for virologic response (proportion of individuals achieving <50 copies/mL) and virologic failure. Exposure–response relationships between these efficacy endpoints and doravirine PK were generally flat over the range of exposures achieved for the 100 mg once-daily regimen in the Phase 3 trials, with a minimal decrease in efficacy in individuals in the lowest 10th percentile of steady-state doravirine concentration at 24 hours values. These findings support 100 mg once daily as the selected dose of doravirine, with no dose adjustment warranted for the studied intrinsic factors.
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