CHIPP-PrEP: Cabotegravir- Hormone Interrogation of Pharmacokinetics-Pharmacodynamics for HIV Prevention

The goal of CHIPP-PrEP: Cabotegravir-Hormone Interrogation of Pharmacokinetics/Pharmacodynamics for HIV Prevention is to characterize the relationship between endogenous and exogenous hormones and long-acting cabotegravir (CAB-LA) for HIV pre-exposure prophylaxis. A key strategy to improve the quality of life for all people at risk of HIV acquisition is to ensure that HIV prevention tools are efficacious for all populations; therefore, more nuanced understanding of drug-hormone interactions is required to understand HIV acquisition vulnerability in the female genital tract and the rectal compartment. The HIV Prevention Trials Network (HPTN) 077 clinical trial revealed sex-based differences in CAB-LA pharmacokinetic (PK) parameters, including trough concentrations (Ctau), maximum concentrations (Cmax), and the area under the concentration curve (AUC); further, the terminal apparent half-life (t1/2) of CAB-LA was longer in females than males. Via population pharmacokinetic (popPK) modeling, CAB-LA PK parameters, including the CAB-LA absorption rate constant (Ka), are influenced by sex, body mass index (BMI) and needle length (indicator of injection site fat distribution). Notably, CAB-LA maximal concentrations (Cmax-SS) are predicted to be lower and Ctau-SS are predicted to be higher in women as compared to men, which may result in protective pharmacologic advantages in women; these observations may be driven by estradiol-mediated changes in fat disposition. While the Phase 2B/3 HPTN 083 and Phase 3 HPTN 084 trials demonstrated superior HIV prevention efficacy of CAB-LA to daily oral emtricitabine/tenofovir disoproxil fumarate (F/TDF) in preventing HIV in males and females, respectively, there was a higher relative risk reduction of HIV acquisition in the HPTN 084 study, which enrolled women. Based on the complex interactions of estrogens on body composition and fat distribution, absence of CAB-LA pharmacologic correlates of protection, and the paucity of data detailing drug interactions between endogenous and exogenous hormones and CAB-LA, additional data are needed to understand the PK and PD of CAB-LA in males and females. The proposed work will address these gaps through the following: a) evaluation of the multi-compartment CAB-LA PK in males and females, including individuals on stable exogenous hormone regimens; b) development of a CAB-LA PK/PD model using ex vivo HIV susceptibility assays; and c) generation of a popPK model inclusive of PK and PD data and subsequent simulations to evaluate the contribution of endogenous and exogenous hormones, such as estradiol, on CAB-LA PK parameters. The proposed research provides a critical next step in our understanding of CAB-LA for HIV prevention and may provide rationale for sex-specific CAB-LA dosing with current and future CAB-LA formulations to optimize protection efficacy.