Adaptive trials in paediatric development: dealing with heterogeneity and uncertainty in pharmacokinetic differences in children

Summary

Aim:  to assess whether an adaptive design in early clinical trials based on the paradigm variable dosing - controlled exposure can provide better dosing recommendations compared to the standard fixed dose approach.

Methods:  in a clinical trial simulation (CTS) setting, a paediatric study was simulated using a pharmacokinetic model previously developed for abacavir. Plasma concentrations following the current recommended dose (8 mg/kg) were taken at standard sampling times, exposures (AUC) were calculated and doses individually adapted to reach the target exposure (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 condition (fixed dose and exposure-controlled) 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 (90^th percentile: 3.13-10.67 mgh/L). A total of 61 subjects out of 128 showed AUC values either too low or to high compared to the target exposure. After dose adjustment, the median exposure was 6.94 mg h/L (5.57-8.25 mg h/L) and 14 subjects showed an exposure outside the target range.

Conclusions:  adaptive randomisation can be used to optimise dosing regimens in early paediatric research. The randomisation of patients to exposures rather than dose increases the probability of demonstrating efficacy (i.e., study power) as compared to dose-controlled trials. Furthermore, it contributes to further understanding of the role of dose on the total heterogeneity in clinical response.

© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society