Lisanne Bevers1, Angela Colbers1, David Burger1, Roeland Wasmann2, Rob ter Heine1
1Radboud University Medical Center, Radboudumc Research Institute for Medical Innovation (RIMI), 2University of Cape Town, Division of Clinical Pharmacology
Objectives: Dolutegravir is a widely used integrase inhibitor for HIV treatment in children and adults. Co-treatment of tuberculosis with rifampicin increases dolutegravir clearance, through induction of UGT1A1 and CYP3A4. This drug-drug interaction can be managed by doubling the dolutegravir dose by administering it twice daily (BID). However, BID dosing can complicate treatment adherence especially for children. In adults, Griesel et al. demonstrated that once-daily (OD) standard-dose dolutegravir, when co-administered with rifampicin, showed comparable virological suppression rates to twice-daily dosing (1). To explore this further for the paediatric population, we developed a population pharmacokinetic model of dolutegravir in children, incorporating intensive PK data from three large paediatric trials. The goal was to characterize the pharmacokinetics of dolutegravir, identify relevant covariates, and assess whether a OD regimen in combination with rifampicin could achieve sufficient dolutegravir concentrations (Ctrough). Methods: We developed a paediatric population pharmacokinetic model of dolutegravir in NONMEM (v7.5) based on intensive pharmacokinetic data from three large paediatric clinical trials i.e. ODYSSEY (NCT02259127), CHAPAS-4 (ISRCTN22964075) and EMPIRICAL (NCT03915366). To account for changes in PK as result of body size, all volume and flow parameters were allometrically scaled to a total body weight of 70 kg. Maturation of dolutegravir clearance in our population was also assessed. Physiologically plausible covariates were tested based on difference in the objective function value (dOFV) and the visual predictive checks (VPC). The confidence intervals of the covariates were estimated using Sampling Importance Resampling (SIR). Simulations were performed with a representative virtual population of 7000 children (3-<40 kg). Our main endpoint was the proportion of children reaching dolutegravir trough levels above the plasma protein binding-adjusted concentration for 90% inhibition (PA-IC90) of 0.064 mg/L, and compare this with the study by Griesel et al (1). Results: The model was developed with 1942 dolutegravir plasma concentrations from 235 children, aged 3 months to 18 years, with concomitant rifampicin use in 36 children. A two-compartment model with first-order elimination and Erlang type absorption (two transit compartments) best described dolutegravir’s pharmacokinetics. Estimated clearance, absorption rate constant and central volume of distribution with relative standard error of estimate (RSE) of 1.82 L/h/70kg (4%), 2.27 h-1 (3%) and 22 L/70kg (4%), respectively. To account for the maturation of clearance in younger children, a broken-stick model best described the maturation of clearance, with adult clearance being reached by 2.67 years. A sigmoidal Emax model was also investigated but parameters could not be estimated with precision. Rifampicin coadministration increased dolutegravir clearance by 61% (95% CI: 47% to 76%). Additionally, we found that children taking film-coated tablets (FTC) without food had similar bioavailability as children taking the dispersible tablets (DT) with food. Children that took FCT with food had 22% (95% CI: 7% to 40%) higher bioavailability compared to without food, while those taking DT with food had 47% (95% CI: 35% to 60%) lower bioavailability than without food. Simulations with our final model, based on the optimal scenario with DT taken without food and FCT taken with food, showed that 94.5% of the children in our virtual population reached dolutegravir trough levels above the PA-IC90 with OD dolutegravir co-administered with rifampicin. Conclusions: Simulations showed that 94.5% of children in the virtual population achieved dolutegravir trough levels above the PA-IC90 with OD dosing co-administered with rifampicin, which compares favourably to the 78% observed in adults (Griesel et al.). These results suggest that OD standard dosing dolutegravir could be an effective treatment option for children with HIV-TB coinfection.
1. Griesel R, Hill A, Meintjes G, Maartens G. Standard versus double dose dolutegravir in patients with HIV-associated tuberculosis: a phase 2 non-comparative randomised controlled (RADIANT-TB) trial. Wellcome Open Res. 2021;6:1.
Reference: PAGE 33 (2025) Abstr 11346 [www.page-meeting.org/?abstract=11346]
Poster: Drug/Disease Modelling - Paediatrics