A population pharmacokinetic model based on HPTN 077 of long‐acting injectable cabotegravir for HIV PrEP

Abstract

Aims Cabotegravir delivered as a long‐acting intramuscular injection has shown superior efficacy to oral tenofovir‐emtricitabine as pre‐exposure prophylaxis (PrEP) for HIV. Cabotegravir pharmacokinetics (PK), like those of other long‐acting depot preparations, exhibit variability between individuals and between injection occasions. The aim of this study is to describe the population pharmacokinetics of long‐acting cabotegravir (CAB‐LA). Methods Using available PK measurements from 133 participants in the HIV Prevention Trials Network (HPTN) 077 trial, we analysed CAB‐LA PK data using nonlinear mixed‐effects modelling to develop a population PK model. Results A two‐compartment model with first order absorption best described the CAB‐LA PK. The analysis identified between‐occasion variability (BOV, i.e., differences in PK within one individual from one injection to the next) as a significant covariate affecting the absorption rate, with an estimated contribution of BOV to PK variability on the absorption rate (ka) of 38.5%. Sex and body weight were identified as significant covariates influencing the absorption rate and apparent clearance of CAB‐LA after intramuscular injection at various doses and frequencies. Male participants had 67% higher ka than female participants. Serially adding to the model body weight on clearance, sex on ka, and BOV on ka led to a decrease in the objective function value (OFV) of 24.4, 36 and 321.4, respectively. Conclusion The public availability of this model will facilitate and enable a wide variety of future clinically relevant simulations to inform the optimal use of CAB‐LA.

Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long‐Acting Intramuscular Injection in Real‐World People with HIV

“…Nonetheless, our PopPK model showed substantial BSV on PK parameters as well as significant IOV on CL. Preliminary analysis revealed an IOV on k a−LA of 28.7%, which was in the same order of magnitude as the value reported by Yu et al 10 However, this model was not stable enough to be implemented. In the absence of more informative data during the absorption phase, the IOV of k a−LA could not be retained in the final model despite the differences in cabotegravir absorption and/or resorption appear to be a likely hypothesis to explain some of the IOV in cabotegravir exposure within subjects (e.g., injection-related variability, 31 as well as physiological differences).…”

“…As previously reported, PK parameters are between HIV-negative participants and PWH in phase III trials. 9,10 Our model-based simulations show that 3-monthly injections of cabotegravir may not consistently provide levels anticipated to be highly protective in the context of PrEP (i.e., above 664 ng/mL). 12,13 In addition, given the significant IOV and BSV demonstrated by our PopPK model, punctual drops in cabotegravir C trough may not be excluded.…”

“…The search for covariates revealed that sex had a highly significant effect on k a−LA , resulting in a lower C trough predicted for females 4 weeks after the loading dose (i.e., at week 8), followed by significantly higher C trough in females from weeks 16 to 48, consistent with previous analyses. 9,10 Males are indeed more likely to have low C trough in the medium term, further modulated by the BMI. The BMI does not take into account fat distribution or muscle anatomy, 32 which arguably makes sex per se the relevant covariate driving differences in cabotegravir absorption.…”

“…Population pharmacokinetic (PopPK) analyses of long-acting cabotegravir based on data from phase IIa/III trials -which included healthy volunteers, HIV-uninfected and at low-risk for HIV, and carefully selected HIV-1 infected individuals -allowed characterizing drug concentration-time profiles by a two-compartment model with first-order absorption and linear elimination, associated with extensive pharmacokinetic (PK) variability. 9,10 Body mass index (BMI) and sex were shown to affect significantly cabotegravir PKs. In particular, the absorption rate constant of i.m.…”

“…cabotegravir was found to be more than 40% slower in females compared with males. 9,10 Considering the inherent "flip-flop" kinetics of longacting cabotegravir, a slower absorption rate would lead to lower peak concentrations, but elevated trough concentrations (C trough ). Therefore, females are expected to have higher C trough of cabotegravir than males and may be at lower risk for subtherapeutic exposure.…”