Adaptive Trials in Paediatric Development: Dealing with Heterogeneity and Uncertainty in Pharmacokinetic Differences in Children

Aims: To assess whether an adaptive design in early clinical trials based on the paradigm of variable dosing and controlled exposure can provide better dosing recommendations compared with the standard fixed dose approach.

Methods: In a clinical trial simulation setting, a paediatric study was simulated using a pharmacokinetic model previously developed for abacavir. Plasma concentrations following the current recommended dose (8 mg kg⁻¹) were taken at standard sampling times, exposures (AUC) were calculated and doses individually adapted to reach the target exposure (i.e. effective exposure in adults). A second round of simulations followed with the adapted doses, and the resulting concentrations were fitted again with the same model. Exposure distributions in both conditions (i.e. fixed dose and controlled exposure) were compared with the target exposure.

Results: The AUC distribution after the current dose resulted in a median exposure of 6.43 mg h l⁻¹ (90th percentile 3.13-10.67 mg h l⁻¹). A total of 61 of 128 subjects showed AUC values either too low or to high compared with the target exposure. After dose adjustment, the median exposure was 6.94 mg h l⁻¹ (5.57-8.25 mg h l⁻¹), and only 14 subjects deviated from the target range.

Conclusions: Adaptive randomization can be used to optimize dosing regimens in early paediatric clinical trials. The randomization of patients to target exposure rather than dose increases the probability of demonstrating efficacy (i.e. study power) compared with dose-controlled trials. Furthermore, it contributes to further understanding of the role of dose on the total heterogeneity in clinical response.