Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics

Abstract

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of doravirine 100 mg was administered to subjects aged 18 to 75 years with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m² (severe renal impairment group) and healthy controls with an eGFR of ≥80 ml/min/1.73 m², matched to the mean of the renal impairment group by age (±10 years) and weight (±10 kg). Doravirine plasma concentrations were determined at regular intervals, and safety was monitored throughout. The geometric mean ratios (90% confidence interval) for severe renal impairment/healthy subjects were 1.43 (1.00, 2.04), 1.38 (0.99, 1.92), and 0.83 (0.61, 1.15) for the plasma doravirine area under the curve from zero to infinity (AUC_0-∞), plasma concentration at 24 h postdose (C₂₄), and maximum plasma concentration (C_max), respectively. Doravirine was generally well tolerated in both groups. Based on the overall efficacy, safety, and PK profile of doravirine, the minor effect of severe renal impairment on doravirine PK observed in this study is not considered clinically meaningful. (This study has been registered at ClinicalTrials.gov under identifier NCT02641067.).

Keywords: HIV; doravirine; pharmacokinetics; renal impairment.

FIG 1

Doravirine arithmetic mean (± standard deviation [SD]) plasma concentration-time profiles on a linear scale (A) and on a semilog scale (B) after single oral doses of doravirine 100 mg to subjects with severe renal impairment and healthy matched control subjects (n = 8 per group); the inset in panel A is for zero to 24 h.

FIG 2

Individual plasma doravirine AUC_0–∞ (A), C_max (B), and C₂₄ (C) values: GM and 95% CIs and GMRs and 90% CIs (severe renal impairment/healthy matched control subjects) following administration of a single oral dose of 100 mg doravirine (n = 8 per group). AUC, area under the plasma concentration-time curve; AUC_0–∞, AUC from predose to infinity; C₂₄, plasma concentration 24 h postdose; CI, confidence interval; C_max, maximum plasma concentration; GM, geometric mean; GMR, geometric mean ratio.