Abstract People with HIV‐1 may find adhering to life‐long daily oral antiretroviral therapy difficult, which can lead to treatment failure or drug resistance. Longer‐acting treatments may improve adherence, treatment outcomes, and quality of life. Islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, plus lenacapavir (LEN), the first‐in‐class HIV‐1 capsid inhibitor, are being evaluated as a weekly oral regimen for HIV‐1. We investigated drug–drug interactions (DDI) between ISL and LEN by evaluating the pharmacokinetics and safety of a single‐dose oral co‐administration of 20 mg of ISL and 600 mg of LEN relative to single‐agent administration in 55 adults without HIV. Co‐administration showed similar pharmacokinetic profiles compared with single‐agent administration; no clinically meaningful pharmacokinetic DDI was identified. The percent geometric least‐squares mean (%GLSM) ratios for ISL exposure parameters were 88%–105%, and corresponding 90% confidence intervals (CIs) were within prespecified bounds (60%–167%). While there were no clinically significant differences in LEN exposure between ISL+LEN and LEN administration, the %GLSM ratios for LEN exposures were 80%–90%, with 90% CIs within 60%–167% except for maximum LEN concentration. High percentage coefficient of variation was observed for LEN pharmacokinetic parameters, resulting in relatively wide 90% CIs. ISL and LEN were generally well tolerated, with no serious or Grade 3 or 4 adverse events, deaths, or discontinuations of the study due to an adverse event. These results and positive initial findings from an ongoing Phase 2 study (NCT05052996) support further clinical development of ISL and LEN as a weekly combination oral treatment for HIV‐1.
Zhang et al. (2026) studied this question.