Exploring the interaction between injection site and biological sex on the real-world population pharmacokinetics of long acting cabotegravir and rilpivirine in people living with HIV

Background Long-acting injectable antiretroviral therapy with cabotegravir and rilpivirine is efficacious though demonstrates large interindividual variability in systemic drug exposure. To better understand the influences of injection and individual factors on drug exposure in a ‘real world’ population, we constructed a population pharmacokinetic model using data from people with HIV in an outpatient clinic setting. Methods We conducted a prospective non-interventional study assessing injected cabotegravir and rilpivirine disposition within the Royal Perth Hospital HIV cohort over a 16-week period. Serum concentrations of cabotegravir and rilpivirine were measured using a validated liquid chromatography tandem mass spectrometry assay. Post injection ultrasound measured the skin to muscle thickness and depot disposition (intramuscular or subcutaneous) following ventrogluteal injection. These data were incorporated into a population pharmacokinetic model. Results 31 individuals were recruited between October 2023 and March 2024. 141 blood samples were collected with 134 unique injection site ultrasounds. Median trough concentrations were 1,390 ng/ml for cabotegravir and 56.0 ng/ml for rilpivirine. Of 134 injections, 40 (30%) were primarily into subcutaneous tissue, occurring more commonly in women. A single compartment model including absorption optimally described cabotegravir pharmacokinetics, with subcutaneous location of depots associated with a 56.3% reduction in absorption rate. Rilpivirine pharmacokinetics fitted optimally to a single compartment model including absorption, with no significant covariates identified. Conclusion Subcutaneous depot deposition after intramuscular injections is not uncommon, occurring more frequently in females and is associated with increased skin to muscle thickness. Slower absorption of cabotegravir from subcutaneous administration contributes to the observed sex differences in drug concentrations.