Comment on: Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV.

We read with great interest the article by Neyens et al.1 published in your journal. This study describes the population pharmacokinetics (PK) modelling strategy of the rilpivirine long-acting (LA) formulation after intramuscular (IM) dosing in healthy and HIV-infected subjects. Data from seven clinical trials were analysed. Briefly, a one-compartment model with linear elimination and two parallel absorption pathways with sequential zero first-order processes adequately captured rilpivirine PK. As stated by the authors, the aim of the study was to quantify the inter- and intra-individual variability and to provide a quantitative assessment of the potential effect of intrinsic and extrinsic factors on rilpivirine exposure. Nevertheless, it is noteworthy that the influence of physiologically plausible covariates (i.e. age, body weight, BMI, sex, race, health status and needle length) was evaluated on absorption parameters only (it is not clear on which parameters). It was stated that a previously developed population PK model for rilpivirine after oral administration in Phase III studies did not identify statistically significant covariates.2 The disposition and elimination being independent of the administration mode, the authors deemed it unnecessary to assess the covariate effects on all pharmacokinetic parameters. However, reading the results of the Crauwels et al. study,2 gender and race were identified as statistically significant covariates on rilpivirine apparent clearance although the authors considered these effects as not clinically significant. Furthermore, in another ‘real-life’ observational population PK study, Néant et al.3 pointed out a rilpivirine half-life two times shorter compared with the one estimated by Crauwels et al.2 from the ECHO/THRIVE Phase III trials. The authors ascribed this discrepancy on half-life to the difference between the ‘real-life’ population coming from therapeutic drug monitoring (TDM) and the population included in the clinical trials.