Background:
Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) being studied for HIV-1 treatment and prevention. Exposure-related decreases in total lymphocytes and CD4+ T-cell counts were observed across ISL clinical trials, with higher frequencies and magnitude of changes observed in ISL higher-dose regimens [20 mg once weekly (QW); 60 and 120 mg once monthly]. Data from Phase 2 and 3 ISL treatment and PrEP trials were used to develop models that describe the changes in lymphocytes and CD4+ T-cells in relationship to intracellular ISL-TP concentrations. Optimized doses were identified to achieve efficacy thresholds and similar CD4+ Tcell and lymphocyte dynamics compared to standard antiretroviral therapy (ART).
Methods:
An ISL popPK model was developed incorporating ISL PK data from once daily (QD) and QW doses. Subsequently an ISL popPKPD model was developed incorporating longitudinal CD4+ T-cell and lymphocyte data from long-term ISL studies. Additionally, CD4+ T-cell changes were summarized across approved ART regimens for the virologically suppressed population to compare to PK/PD model predictions. Revised ISL QW doses were selected based on simulated doses providing ISL exposures ensuring coverage for WT and M184V variants as well as CD4 and Lymph counts changes comparable to standard ART in switch population.
Results:
The ISL population PK model was updated with additional phase 1 studies and the Phase 3 QD HIV trials and captures both plasma ISL and intracellular ISL-TP dynamics across regimens. The CD4+ T cell and lymphocyte models were developed and captures the changes for treatment naïve, virologically suppressed, and prevention populations on standard therapy. The CD4+ T cell model captured the ISL changes ISL in the daily treatment Phase 2 and 3 studies and the lymphocyte model additionally captured the ISL changes for the Phase 2 PrEP trial. The summary of switch trials show that the majority of trials have CD4+ T cell changes that fall between -5 and +10% changes over the course of the trials and allowed for benchmarking of the CD4+ T cell model simulations. Simulations of the models were conducted for ISL 0.5-20 mg QW predicting ISL-TP exposures and CD4+ T cell and lymphocyte changes.
Conclusions:
ISL 2 mg QW is predicted to rapidly achieve efficacious exposures for wild-type and M184I/V HIV variants and have similar CD4+ T cell and lymphocyte changes as standard ART for virologically suppressed PWH.