CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

642

Pharmacokinetic Modeling of Missed Dose Scenario of Oral Weekly Islatravir Plus Lenacapavir Dhananjay Marathe 1 , Diane Longo 2 , Haeyoung Zhang 1 , Nieves Velez de Mendizabal 1 , Ryan Vargo 2 , Hadas Dvory-Sobol 1 , Randolph Matthews 2 , Martin 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 µ M) 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. Rhee 1 , Cyril Llamoso 2 , Gillian Gillespie 2 , Marjorie Imperial 1 1 Gilead Sciences, Inc, Foster City, CA, USA, 2 Merck & Co, Inc, Rahway, NJ, USA

ISL-triphosphate (TP) concentrations were used to optimize the QW dose for HIV treatment. ISL 2 mg QW was predicted to achieve efficacy thresholds and similar lymphocyte and CD4+ T-cell dynamics compared to standard antiretroviral therapy (ART). Subsequently, a Phase 2 study was initiated (GS-US-563-6041, N=104) with virologically suppressed (VS) people with HIV-1 randomized 1:1 to switch from once-daily (QD) oral bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) to oral QW ISL 2 mg + lenacapavir (LEN) 300 mg. Methods: Simulations were performed using a previously developed ISL PopPK model, with observed ISL plasma PK for Phase 2 participants as input, to predict ISL-TP exposures in Phase 2 participants. Previously developed ISL PK/PD models were used to simulate lymphocyte and CD4+ T cell counts using PopPK predicted ISL-TP exposures for Phase 2 participants as input. Results: Observed ISL plasma PK exposures for Phase 2 participants were consistent with exposures predicted for 2 mg QW in simulations performed prior to the Phase 2 study (Figure 1A). Simulations performed using the ISL PopPK model with observed ISL plasma PK for Phase 2 participants as input demonstrated that all Phase 2 participants achieved ISL-TP exposures above the inhibitory quotient (IQ)5 (1.25 µM) for M184V/I variants and IQ5 (0.25 µM) for wild-type (WT) HIV-1 (Figure 1B). As predicted, achieving these exposures resulted in high rates of participants maintaining virologic suppression through Week 24 in the Phase 2 study. ISL-TP exposures achieved in Phase 2 were below levels predicted by the PK/PD models to have lymphocyte and CD4+ T cell effects. No between-group differences in lymphocyte and CD4+ T cell changes were observed in Phase 2. Conclusions: Phase 2 efficacy and lymphocyte and CD4+ T-cell results are consistent with predictions that QW 2 mg ISL in combination with LEN is highly efficacious and there were no between-group differences in lymphocyte or CD4+ T-cell changes from baseline to Week 24. ISL/LEN 2/300 mg is proceeding into Phase 3 with the potential to be the first oral QW treatment option. Can “Equivalence” of a Generic Cabotegravir LA Be Inferred From a Shortened Pharmacokinetic Study? Henry Pertinez 1 , Rajith Rajoli 1 , Andrew Lloyd 1 , Charles W. Flexner 2 , Andrew Owen 1 1 University of Liverpool, Liverpool, UK, 2 The Johns Hopkins University School of Medicine, Baltimore, MD, USA Background: Long acting injectable (LAI) antiretrovirals hold enormous potential for treatment and prevention of HIV in low- and middle-income countries (LMIC) but significant access challenges exist. One obstacle for generic LAIs is the assessment of “equivalence” with originator products. Accepted standards of bioequivalence for oral generic products may be sub-optimal because small differences may be accentuated over long dosing intervals, and the need for phase III studies would present major funding and timeline obstacles to access. Partial AUCs and/or truncated pharmacokinetic (PK) assessments have been postulated as possible approaches to accelerate approval of generic LAIs. The current study sought to assess potential feasibility of such an approach through re-analysis of published PK for cabotegravir (CAB) LAI. Methods: A single 800 mg dose CAB LAI plasma PK profile (32 week duration) from the literature was fitted with an empirical PK model. A 1-compartment disposition model was used, and profile shape warranted a 2-fraction 1st order input depot release. Repeated fits successively truncating the last timepoint of the profile from the dataset were undertaken. PK model parameter estimates for truncated profiles were then compared to those from the full profile. Results: Adequate fitting of the model was obtained. With the dataset truncated up to the first 12 weeks, parameter estimates remained within 10% deviation from those obtained using the full profile (Table 1). Truncation to

Poster Abstracts

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643

Modeling Accurately Predicts Efficacious Islatravir QW Dose With No Lymphocyte and CD4 Changes Diane Longo 1 , Michelle Pham 1 , Marjorie Imperial 2 , Gillian Gillespie 1 , Stephanie Klopfer 1 , Randolph Matthews 1 , Cyril Llamoso 1 , Elizabeth Rhee 1 , Martin Rhee 2 , Dhananjay Marathe 2 , Ryan Vargo 1 1 Merck & Co, Inc, Rahway, NJ, USA, 2 Gilead Sciences, Inc, Foster City, CA, USA Background: Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) being studied for HIV-1 treatment. Exposure-related decreases in total lymphocyte and CD4+ T-cell counts were observed across ISL clinical trials, with greater changes observed in ISL higher-dose regimens. Models that describe changes in lymphocytes and CD4+ T-cells in relation to intracellular

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