Background
In a Phase 2 study, oral once-weekly (QW) islatravir (ISL) plus lenacapavir (LEN) maintained high rates of viral suppression at 24 weeks in people with HIV-1 who were virologically suppressed (NCT05052996; Colson et al. CROI 2024; Abstract 208). To maintain high rates of viral suppression, it is important to ensure optimal drug concentrations in the event of missed doses.
Methods
ISL-triphosphate (ISL-TP) simulations used an existing population pharmacokinetic (PK) model developed using oral ISL PK data from ISL Phase 1–3 studies. Similarly, LEN simulations used an existing single-agent model developed with intravenous, oral, and subcutaneous LEN PK data. The reference scenario was dosing with 1 mg ISL and 600 mg LEN on Day (D)1 and D2 (corresponding to two tablets of ISL/LEN 0.5/300 mg fixed dose combination [FDC] on each day), followed by 2 mg ISL and 300 mg LEN (corresponding to one tablet of ISL/LEN 2/300 mg FDC) QW starting on D8 as a maintenance dose. Simulations under steady state conditions were performed to estimate the impact of various durations of missed doses and make-up dose strategies. These were compared against the reference scenario as well as efficacy and clinically established safety exposure thresholds, as appropriate, to guide missed dose recommendations for Phase 3 studies. For ISL-TP, the target was to ensure that the 90% prediction interval (PI) for ISL-TP exposures remained above the inhibitory quotient (IQ)5 (1.25 µM) for M184V/I variants and IQ5 (0.25 µM) for wild-type HIV-1, and below exposures associated with decreases in total lymphocyte and CD4+ T-cell counts. For LEN, the target was to ensure the 90% CI for mean plasma concentration projections was consistently above the 4-fold in vitro protein binding-adjusted 95% effective concentration (IQ4; 15.5 ng/mL).
Results
Simulations demonstrated that both ISL-TP and LEN maintained optimal concentrations one week after a missed dose at steady state (Figure). After one full missed dose (14 days after last dose), the simulated median trough concentration for ISL-TP was 2.16 µM (90% PI: 1.45–5.15), and the simulated mean trough concentration for LEN was 20.7 ng/mL (90% CI: 19.4–22.9), well above the target concentrations of 1.25 µM and 15.5 ng/mL, respectively.
Conclusions
The analysis showed that people with HIV-1 who miss one dose of 2/300 mg ISL/LEN FDC can continue treatment and maintain optimal drug concentrations, allowing for a one-week forgiveness window.
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