Doravirine is a novel, potent, HIV-1 non-nucleoside reverse transcriptase inhibitor that is primarily metabolized by oxidation via CYP3A4 with limited renal excretion. As the HIV-infected population ages, the number of HIV-infected patients with chronic kidney disease will also increase. Even drugs with limited renal excretion have exhibited altered pharmacokinetics (PK) in patients with severe renal impairment. This study assessed the impact of severe renal impairment on the PK of doravirine.
This was an open-label, single-dose study in subjects with severe renal impairment and healthy matched control subjects. The healthy control subjects were matched within +/-10 kg and +/-10 years of the mean weight and age, respectively, of the severe renal impairment cohort. A single dose of 100 mg doravirine was administered to subjects with severe renal impairment (eGFR < 30 mL/min/1.73 m^2) and to healthy matched controls (eGFR ≥ 80 mL/min/1.73 m^2). Blood samples to measure doravirine concentrations were collected through 96 and 72 hours postdose in renally impaired subjects and healthy controls, respectively.
Sixteen (16) adult subjects were enrolled; 8 (2 female, 6 male) with severe renal impairment and 8 (3 female, 5 male) healthy matched control subjects. In the subjects with severe renal impairment, AUC0-inf, and C24hr were modestly increased, while Cmax was minimally impacted. The geometric mean ratios (90% confidence intervals) [severe renal impairment/healthy] for doravirine Cmax, AUC0-inf, and C24hr were 0.83 (0.61, 1.15), 1.43 (1.00, 2.04), and 1.38 (0.99, 1.92), respectively. Terminal t1/2 was increased from 17 for healthy matched control subjects to 25 hrs for the subjects with severe renal impairment. There were no serious adverse experiences (AEs). Three (19%) subjects reported one AE each; only 1 of these (mild nausea) occurring in a subject with renal impairment was considered drug related. No subjects discontinued.
Severe renal impairment had a modest, but not clinically meaningful, effect on the PK of doravirine. A single dose of 100 mg doravirine was generally well tolerated in subjects with severe renal impairment.