Lenacapavir (LEN, GS-6207), a novel, first-in-class, selective inhibitor of HIV-1 capsid function, is in clinical development for the treatment and prevention of HIV-1 infection. Both preclinical and clinical observations suggest fecal excretion as the primary pathway, with renal excretion as a minor pathway of LEN elimination (<1% of dose). This Phase 1 study evaluated the pharmacokinetics (PK) of single oral dose LEN in participants with severe renal impairment (RI) to inform LEN dosing in people with impaired renal function.
Ten participants with stable, severe RI (creatinine clearance by Cockcroft-Gault method [CrCl] 15 to ? 29 mL/min) and 10 healthy matched controls (HMC) with normal renal function received a single oral dose of LEN (300 mg) on Day 1. Plasma concentrations of LEN were collected over 48 hours on Day 1 with single PK samples collected anytime on Days 4, 6, 8, 15, 22, 29, 36, 43, and 50, quantified by validated LC-MS/MS methods. Geometric least squares mean ratios (GLSMRs) and 90% confidence intervals (CIs) of AUC[sub]inf[/sub], AUC[sub]last[/sub], and C[sub]max[/sub] were calculated to compare PK changes in participants with severe RI versus HMC. Plasma protein binding of LEN was evaluated. Safety (adverse events [AEs], clinical lab assessments, and vital signs) was monitored throughout the study.
In participants with severe RI (median CrCl = 21.9 mL/min), exposures (AUCinf, AUClast, and Cmax) of LEN were 84%, 89%, and 162% higher, respectively, relative to HMC with normal renal function (median CrCl = 98.4 mL/min) (Figure). Unbound fractions (~0.2%) of LEN were similar between severe RI and HMC groups. LEN was generally well tolerated in both groups. No participant experienced serious or Grade 4 AEs, or AEs leading to premature discontinuation of study drug. One participant in the severe RI group experienced a serious Grade 1 AE of melena, which resolved and was not considered related to study drug.
LEN was generally well-tolerated. LEN exposure was moderately higher in participants with severe RI compared to HMC. These increases, despite renal excretion being a minor pathway of LEN elimination, were potentially due to the broader effect of uremic toxins on P-gp (ie, decreased activity of P-gp-mediated LEN transport) and alterations in metabolic enzymes. Based on the totality of available LEN safety data across clinical studies, the moderate increase in LEN exposure was not deemed clinically meaningful.