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Aim: To characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability., Methods: Analyses were implemented in NONMEM and R. Concentrations below the quantitation limit were modelled with likelihood-based approaches. Covariate relationships were evaluated using forward addition (P < .01) and backward elimination (P < .001) approaches. The impact of each covariate on trough and peak concentrations was evaluated through simulations. External validation was performed using prediction-corrected visual predictive checks., Results: The model-building dataset included 23 926 plasma concentrations from 1647 adult HIV-1-infected (72%) and uninfected (28%) subjects in 16 studies at seven dose levels (oral 10-60 mg, long-acting [LA] intramuscular injection 200-800 mg). A two-compartment model with first-order oral and LA absorption and elimination adequately described the data. Clearances and volumes were scaled to body weight. Estimated relative bioavailability of oral to LA was 75.6%. Race and age were not significant covariates. LA absorption rate constant (KA LA ) was 50.9% lower in females and 47.8% higher if the LA dose was given as two split injections. KA LA decreased with increasing BMI and decreasing needle length. Clearance was 17.4% higher in current smokers. The impact of any covariate was ≤32% on trough and peak concentrations following LA administration. The final model adequately predicted 5097 plasma concentrations from 647 subjects who were not included in the model-building dataset., Conclusions: A cabotegravir population pharmacokinetic model was developed that can be used to inform dosing strategies and future study design. No dose adjustment based on subject covariates is recommended., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background CAB is an integrase strand transfer inhibitor under investigation as an injectable LA formulation for the treatment and prevention of HIV, and as a tablet formulation as an oral lead-in (OLI) and bridging treatment for dose interruptions. The monthly injection regimen of CAB LA and rilpivirine (RPV) LA was noninferior to standard oral therapy in maintaining HIV-1 suppression in Phase 3 trials. PPK modeling and simulation was used to inform strategies for managing dosing interruptions. Methods A 2-compartment model with first-order oral and LA absorption and elimination adequately described the data from 1,647 healthy (28%) and HIV-infected (72%) adult subjects in 16 studies. Gender was a significant covariate on LA absorption; therefore, simulations of 5,000 virtual subjects were performed using a 4:1 male:female ratio to ensure 1,000 representative females and covariate sampling with replacement from the analysis dataset. One- to 12-week delays in dosing of the second, third, and fourth injection were simulated, and predicted troughs were compared with the 5th percentile (0.65 μg/mL) of trough concentrations following the first injection in Phase 3. Simulations of 1–2 months of oral bridging with CAB 30 mg once daily from time of a missed injection until CAB LA dosing resumed were performed, with the median Cmax (13.1 μg/mL) observed following oral CAB 60mg once daily in Phase 2b as an upper reference. Results Proportions of subjects predicted to achieve target plasma CAB trough concentrations are shown by length of delay and injection visit in Table 1. Oral bridging with CAB 30mg once daily starting at the time of a planned missed injection is predicted to provide exposures within ranges observed in clinical studies (Figure 1). Conclusion Dosing delays of up to one week appear to have minimal impact, but the effect is more likely to become problematic with longer delays, particularly in the first few months of dosing. Oral bridging provides therapeutic and safe exposures for planned interruptions in LA dosing. Regardless of use of oral bridging, simulations support resuming CAB LA dosing for interruptions <1 month (<2 months between injections) and reinitiating CAB LA with a loading dose and subsequent monthly injections for interruptions ≥ 1 month (≥ 2 months between injections). Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]