Simulation-Based Predictions to Support the Development of a Pediatric Fixed-Dose Combination of...

Approximately 1.4 million children (aged 0-14 years) are living with human immunodeficiency virus, most infected through mother-to-child transmission. Despite the availability of combination antiretroviral treatment, only 57% of children had access to combination antiretroviral treatment in 2023, with suboptimal formulations contributing to high mortality. Limited access to age-appropriate formulations is a key barrier, particularly in low- and middle-income countries. This study presents stochastic simulations with previously published population pharmacokinetic models to determine an optimal fixed-dose combination (FDC) ratio of dolutegravir (DTG), emtricitabine (FTC), and tenofovir alafenamide (TAF) for children weighing 3-20 kg. For children weighing more than 20 kg, the use of the adult FDC formulation is proposed.

Population pharmacokinetic models were used for exposure simulation of DTG, TAF, and its metabolite tenofovir. The adequacy of the proposed FDC was based on whether the simulated drug exposures met predefined efficacy and safety targets. For DTG, the minimum trough concentration target of 0.32 mg/L; for TAF, the area under the curve (AUC) target of 55 ng*h/mL; and for tenofovir, the maximum AUC of 2586 ng*h/mL were used. Simulated exposures were also compared to adult reference values: geometric mean trough concentration for DTG (0.83 mg/L), median AUC for TAF (185 h*ng/mL), and median AUC for tenofovir (256 h*ng/mL). The US Food and Drug Administration-recognized dosing range for FTC was used to verify appropriate dosing in each weight band.

The modeling approach identified a practical FDC dosing ratio for children across weight bands (3-20 kg). Simulated DTG exposure exceeded the minimum target in over 98% of cases, while TAF exposure met the efficacy threshold in more than 90% of children. Tenofovir exposure remained below toxic concentrations in all weight bands, ensuring safety. In a small subset of children aged under 3 months, FTC doses exceeded the approved maximum, though overall dosing remained within safe limits.

This paper presents a modeling approach to determine an optimal FDC ratio for pediatric DTG/FTC/TAF. The strategy predicted effective drug exposure and safety across age and weight bands, supporting the development of a child-friendly FDC that could accelerate access to human immunodeficiency virus treatment in low- and middle-income countries. This dosing regimen is being further evaluated in the UNIVERSAL-1 clinical trial.