TY - JOUR
AU1 - Abdalla, Seef
AU2 - Compagnucci, Alexandra
AU3 - Zheng, Yi
AU4 - Tréluyer, Jean-Marc
AU5 - Saidi, Yacine
AU6 - Ramos, José T
AU7 - Coelho, Alexandra
AU8 - Riault, Yoann
AU9 - Cressey, Tim R
AU1 - Hirt, Déborah
AU1 - ,
AB - BackgroundSMILE, a multicentre randomized trial, compared the efficacy and safety of switching virologically suppressed children and adolescents with HIV to a once-daily dual regimen of dolutegravir plus ritonavir-boosted darunavir versus continuing standard ART. Within a nested pharmacokinetic (PK) substudy, we performed a population PK analysis to describe total and unbound dolutegravir plasma concentrations in children and adolescents receiving this dual therapy.MethodsSparse blood samples were obtained during follow-up for dolutegravir quantification. A population PK model was developed to simultaneously describe total and unbound dolutegravir concentrations. Simulations were performed and were compared with the protein-adjusted 90% inhibitory concentration (IC90) and the in vitro IC50, respectively. Dolutegravir exposures in children aged ≥12 years were also compared with values in treatment-experienced adults.ResultsFour hundred and fifty-five samples from 153 participants aged between 12 and 18 years were collected for this PK analysis. A one-compartment model with first-order absorption and elimination best described unbound dolutegravir concentrations. The relationship between unbound and total dolutegravir concentrations was best characterized by a non-linear model. Unbound dolutegravir apparent clearance was significantly influenced by total bilirubin concentrations and by Asian ethnicity. All children and adolescents had trough concentrations well above the protein-adjusted IC90 and the in vitro IC50 values. Dolutegravir concentrations and exposures were also similar to those obtained in adults receiving dolutegravir 50 mg once daily.ConclusionsA once-daily 50 mg dolutegravir dose for children and adolescents produces adequate total and unbound concentrations when used as part of dual therapy with ritonavir-boosted darunavir.
TI - Population pharmacokinetics of unbound and total dolutegravir concentrations in children aged 12 years and older: a PK substudy of the SMILE trial
JF - Journal of Antimicrobial Chemotherapy
DO - 10.1093/jac/dkad043
DA - 2023-03-03
UR - https://www.deepdyve.com/lp/oxford-university-press/population-pharmacokinetics-of-unbound-and-total-dolutegravir-PnK0iQ8XGj
SP - 1041
EP - 1049
VL - 78
IS - 4
DP - DeepDyve
ER -