Abstract Body

Co-administration of islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, and lenacapavir (LEN), a capsid inhibitor, has the potential to offer a safe and efficacious oral once weekly regimen for the treatment of HIV-1 infection. ISL is not a substrate of cytochrome P450 (CYP) enzymes and is primarily metabolized via adenosine deaminase, with significant elimination via urinary excretion; ISL also has no effect on CYP enzymes or major transporters. LEN is a substrate of CYP3A, uridine diphosphate-glucuronosyl transferase 1A1, and P-glycoprotein transporter, and is a moderate inhibitor of CYP3A. Available data indicate that significant systemic drug-drug interactions (DDIs) between ISL and LEN are unlikely. This clinical study examined potential DDIs between ISL and LEN following oral co-administration.

A Phase 1, open label, parallel design, single dose, three-cohort study was conducted in 56 healthy volunteers, who received single oral doses of co-administered ISL 20 mg and LEN 600 mg (test), ISL 20 mg alone (reference), or LEN 600 mg alone (reference). Plasma pharmacokinetic (PK) samples were collected up to Day 12 for ISL and Day 43 for LEN and analyzed with high-performance liquid chromatography tandem mass spectrometry using validated methods. DDI assessment was performed using the geometric least-squares mean (GLSM) ratios and 90% confidence intervals (CIs) of test versus reference treatments. With 15 evaluable participants per cohort, no-effect boundaries were defined as 60%-167%, with ? 90% power assuming %CV of 41.4% based on ISL area under the curve (AUC) from a previous study.

Co-administration of ISL and LEN was generally well-tolerated, with no serious or severe adverse events or clinically significant grade 3-4 lab abnormalities. Preliminary results based on nominal times for %GLSM ratios (90% CI) of PK parameters AUCinf and Cmax for ISL were 105% (90.2-123%) and 87.9% (68.7-113%), respectively, and for LEN 88.6% (60.5-130%) and 80.1% (50.9-126%), respectively. Higher %CV was observed for LEN compared to ISL, resulting in a wider 90% CI. Point estimates of %GLSM ratios and 90% CIs show that PK of ISL and LEN are similar when administered alone or in combination.

Preliminary data showed no significant DDIs for oral co-administration of ISL and LEN. Data from this study support the ongoing clinical development of co-administered ISL and LEN as a combination therapy for treatment of HIV-1 infection.