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AimTo 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.MethodsAnalyses 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

Aims: Cabotegravir is an integrase strand transfer inhibitor in clinical development as long‐acting (LA) injectable HIV preexposure prophylaxis. Methods: This phase I study assessed pharmacokinetics of cabotegravir in plasma and anatomical sites associated with sexual HIV‐1 transmission after repeated oral and single intramuscular (IM) LA dosing in healthy adults. Following a 28‐day oral lead‐in period of cabotegravir 30 mg and a washout period of 14–42 days, participants were administered a single ultrasound‐guided gluteal IM cabotegravir LA 600‐mg injection. The study objective was to characterize cabotegravir concentrations in plasma, cervical, vaginal and rectal tissues, and cervicovaginal and rectal fluids and up to Week 12 after IM injection. Results: Nineteen participants enrolled and 16 completed the study through Week 52. Cabotegravir was detected in plasma and all tissues and fluids. Median plasma cabotegravir concentrations exceeded the in vitro protein‐adjusted 90% maximal inhibitory concentration through Week 12. Median tissue‐ and fluid‐to‐plasma cabotegravir concentration ratios across all visits were 0.32 for rectal fluid and 0.08–0.16 for other tissues and fluids. Adjusted R2 coefficients between cabotegravir concentrations in plasma and cervical, vaginal and rectal tissues were 0.78, 0.79 and 0.90, respectively. Injection‐site reactions were common (88% of participants) and were mostly grade 1 in intensity (82%). Two participants reported 11 non–drug‐related serious adverse events. Conclusion: Concentrations of cabotegravir in tissues and fluids were proportional to plasma over time, with strong correlations between tissue and plasma concentrations. Cabotegravir LA tissue‐to‐plasma ratios may be important for understanding its use as preexposure prophylaxis. [ABSTRACT FROM AUTHOR]

Aim: Cabotegravir long‐acting (LA) intramuscular (IM) injection is being investigated for HIV preexposure prophylaxis due to its potent antiretroviral activity and infrequent dosing requirement. A subset of healthy adult volunteers participating in a Phase I study assessing cabotegravir tissue pharmacokinetics underwent serial magnetic resonance imaging (MRI) to assess drug depot localization and kinetics following a single cabotegravir LA IM targeted injection. Methods: Eight participants (four men, four women) were administered cabotegravir LA 600 mg under ultrasonographic‐guided injection targeting the gluteal muscles. MRI was performed to determine injection‐site location in gluteal muscle (IM), subcutaneous (SC) adipose tissue and combined IM/SC compartments, and to quantify drug depot characteristics, including volume and surface area, on Days 1 (≤2 hours postinjection), 3 and 8. Linear regression analysis examined correlations between MRI‐derived parameters and plasma cabotegravir exposure metrics, including maximum observed concentration (Cmax) and partial area under the concentration–time curve (AUC) through Weeks 4 and 8. Results: Cabotegravir LA depot locations varied by participant and were identified in the IM compartment (n = 2), combined IM/SC compartments (n = 4), SC compartment (n = 1) and retroperitoneal cavity (n = 1). Although several MRI parameter and exposure metric correlations were determined, total depot surface area on Day 1 strongly correlated with plasma cabotegravir concentration at Days 3 and 8, Cmax and partial AUC through Weeks 4 and 8. Conclusion: MRI clearly delineated cabotegravir LA injection‐site location and depot kinetics in healthy adults. Although injection‐site variability was observed, drug depot surface area correlated with both plasma Cmax and partial AUC independently of anatomical distribution. [ABSTRACT FROM AUTHOR]