Population pharmacokinetics of cabotegravir following oral administration and long-acting intramuscular injection in real-world people with HIV. Clinical Pharmacology & Therapeutics
Thoueille et al. aimed to characterize the concentration-time profile of long-acting cabotegravir and its associated variability among people with HIV (PWH) in the SHCS and therefore to build real-world reference percentile curves of cabotegravir concentrations that can be used to support the interpretation of therapeutic drug monitoring (TDM) results in PWH receiving this treatment.
Adults (>18 years old) receiving long-acting cabotegravir/rilpivirine enrolled in the SHCS were included. Blood sampling and last administration times, dosage, individual body weight (BW), height, and BMI were recorded
Overall, 238 PWH contributed to 1’038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). The model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady- state of 8 months and an elimination half-life of 4.6 weeks for long-acting cabotegravir. Sex and body mass index significantly influenced absorption, and body weight affected clearance. Model-based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4-fold protein-adjusted 90% inhibitory target concentration.
In conclusion, the proposed population pharmacokinetic model shows a faster absorption rate constant and elimination than previously described, resulting in lower trough concentrations of cabotegravir. Sex was found to have a strong effect on the long-acting cabotegravir absorption rate. The analysis highlights discrepancies in pharmacokinetic between clinical trial participants and people with HIV followed in a routine clinical setting, and provides the basis for further studies on their implications for clinical care. In addition, simulations show that 3-monthly injections of cabotegravir might not consistently provide exposure levels ensuring effectiveness.