Lenacapavir (LEN, GS-6207), a potent, selective, first-in-class, multi-stage inhibitor of HIV-1 capsid function is in clinical development as a long acting agent to treat HIV-1 infection, supporting weekly (oral LEN) or less frequent dosing (subcutaneous LEN). In people living with HIV, LEN has shown potent antiviral activity and is well tolerated. This study was conducted to evaluate the effect of moderate hepatic impairment (HI) on the pharmacokinetics (PK) of oral LEN to inform dosing recommendations in patients with mild and moderate HI.
Participants with moderate HI (Child-Pugh Turcotte [CPT] classification B; score 7-9) and healthy controls (HC) matched for age (±10 years), sex, race and BMI (±15%) received a single oral dose of LEN 300 mg with food (moderate fat meal). Plasma PK was collected through Day 92 post dose; protein binding of LEN was assessed. Preliminary PK parameters were estimated using noncompartmental analysis, and geometric least squares mean (GLSM) ratios and 90% confidence intervals (CI) for AUCinf and Cmax were calculated (GLSM: HI:HC). Safety was evaluated throughout the study.
20 participants (N=10 with moderate HI and N=10 HC) were enrolled in the study. Preliminary LEN exposure, as assessed by AUCinf and Cmax, was ~1.5-fold and ~2.6-fold higher respectively, in subjects with moderate HI, as compared to HC (Table 1). LEN plasma protein binding, median Tmax and t1/2 were similar in both groups. Exploratory analyses indicated no relevant relationships between LEN exposure and CPT score or individual elements of CPT classification. Additionally, no correlation is observed between LEN exposure and subjects’ weight or age. Study treatment was well tolerated. No participant experienced serious or Grade 3 or 4 treatment emergent adverse events. Four HI and one HC participants experienced Grade 3 or 4 lab abnormalities, none of which were considered clinically relevant. All Grade 3 or 4 laboratory abnormalities improved on the next visit and/or were preexisting.
LEN AUC and Cmax were 1.5- and 2.6-fold higher respectively, in moderately hepatically impaired participants as compared to healthy controls. Based on cumulative safety data in the LEN SC and oral clinical program, no dose adjustment of LEN is recommended in patients with mild to moderate hepatic impairment.