Adaptive trials in paediatric development: dealing with heterogeneity and uncertainty in pharmacokinetic differences in children
Article first published online: 10 JUL 2012
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 74, Issue 2, pages 346–353, August 2012
How to Cite
Cella, M., Danhof, M. and Della Pasqua, O. (2012), Adaptive trials in paediatric development: dealing with heterogeneity and uncertainty in pharmacokinetic differences in children. British Journal of Clinical Pharmacology, 74: 346–353. doi: 10.1111/j.1365-2125.2012.04187.x
- Issue published online: 10 JUL 2012
- Article first published online: 10 JUL 2012
- Accepted manuscript online: 18 JAN 2012 10:56AM EST
- Received; 20 September 2011; Accepted; 6 January 2012; Accepted Article Published Online; 18 January 2012
- adaptive design;
- dose adjustment;
- model-based drug development;
- paediatric drug development;
- paediatric drug prescription;
- pharmacokinetic bridging
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• In children, differences in treatment response may be influenced by the effect of developmental changes and maturation on drug disposition, which lead to ambiguous relationships between dose and exposure.
• Initial estimation of the paediatric dose is obtained by extrapolation. However, no consensus on dose selection methodologies has been reached so far.
• The paradigm compound used in this investigation is abacavir, a nucleoside reverse transcriptase inhibitor used to treat human immunodeficiency virus infection. The recommended paediatric dose is 8 mg kg−1 twice daily up to a maximum of 300 mg twice daily.
WHAT THIS STUDY ADDS
• The use of adaptive rather than fixed dose protocols enables the accurate selection of the paediatric dose.
• Adaptive procedures ensure shrinkage of the observed exposure distribution around the target range irrespective of study size.
• Modelling and simulation techniques provides the basis for the systematic evaluation of the implications of dose selection in a paediatric clinical trial.
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.