Once daily dosing of dolutegravir in combination with rifampicin in infants and children living with HIV: A population pharmacokinetic approach

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Once daily dosing of dolutegravir in combination with rifampicin in infants and children living with HIV: A population pharmacokinetic approach

Lisanne Bevers¹, Angela Colbers¹, David Burger¹, Chishala Chabala², Alfeu Passanduca³, Victor Musiime⁴, Hilda Mujuru⁵, Anna Turkova⁶, Alasdair Bamford⁷ and Rob ter Heine¹

¹Department of Pharmacy, Radboud Institute for Medical Innovations (RIMI), Radboud University Medical Center; ²Department of Paediatrics and Child Health, School of Medicine, University of Zambia; ³Universidade Eduardo Mondlane Faculdade de Medicina; ⁴Research Department, Joint Clinical Research Centre; ⁵Clinical Research Centre, Faculty of Medicine and Health Sciences, University of Zimbabwe; ⁶Medical Research Council Clinical Trials Unit at University College London; ⁷Great Ormond Street Hospital for Children NHS Foundation Trust

Background: Dolutegravir clearance is increased in presence of rifampicin, due to induction of UGT1A1 and CYP3A4. This drug–drug interaction between rifampicin and dolutegravir can be overcome by twice-daily dolutegravir dosing with daily dose doubled. However, twice-daily dosing complicates treatment adherence, once-daily being preferred for children. Griesel et al. (2023) showed comparable virological suppression rates of once-daily dosing of dolutegravir vs. twice-daily dosing in combination with rifampicin in adults. We therefore aimed to establish a potential once-daily dosing regimen for dolutegravir co-administered with rifampicin for use in the paediatric population.

Methods: We developed a paediatric population pharmacokinetic model of dolutegravir in NONMEM based on intensive pharmacokinetic data from three large paediatric clinical trials, that is, ODYSSEY (NCT02259127), CHAPAS-4 (ISRCTN22964075) and EMPIRICAL (NCT03915366). The model was developed with 2522 dolutegravir plasma concentrations from 235 infants and children aged 3 months to 17 years, with concomitant rifampicin use in 36 subjects. To account for changes in pharmacokinetics as result of body size, all volume and flow parameters were allometrically scaled to a total body weight of 70 kg. Maturation of UGT1A1-mediated 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 (VPCs). A representative virtual population with 7000 children (3 to <40 kg), equally distributed among different weight bands and formulations, was developed to perform the once-daily dosing simulations. Dosing of dolutegravir was based on the current World Health Organization (WHO) weight-band dosing recommendations. Our main outcome focused on the percentage of children reaching dolutegravir trough levels above the PA-IC90 of 0.064 mg/L.

Results: A one-compartment model with first-order elimination and Erlang-type absorption (two transit compartments) best described dolutegravir's pharmacokinetics. In our population, we estimated clearance, absorption rate constant and distribution volume with relative standard error of estimate (RSE) of 2.37 L/h (4.8%), 2.19 h⁻¹ (4%) and 27.5 L (4.4%), respectively. Rifampicin co-administration increased dolutegravir clearance by factor 1.45 (RSE 11.6%). Dispersible tablets had 74% (RSE 8%) higher bioavailability vs. film-coated tablets, whereas administration with food increased the bioavailability of film-coated tablets by 35% (RSE 8%) and decreased the bioavailability of dispersible tablets by 39.8% (RSE 9%). Simulations with our final model showed that 92.7% of the children in our virtual population reached dolutegravir trough levels above the PA-IC90 with once-daily dolutegravir (without food) co-administered with rifampicin compared to 81% in adults reported at week 24 in the study of Griesel et al.

Conclusions: Simulations based on our model suggest that once-daily dolutegravir co-administered with rifampicin has potential for children living with HIV. Therapeutic target attainment (above the PA-IC90) in the paediatric population is higher than what was observed in adult clinical data showing similar efficacy compared to twice-daily dolutegravir in co-administered with rifampicin. Further analysis of individual weight bands and other dosage scenarios are currently in process.