Abstract
METHODS
Using an adult pharmacokinetic model, clinical trial simulations were performed to determine the power of a proposed clinical trial design. Power was defined as the fraction of 1000 trials with an area under the plasma concentration-time curve at steady-state (AUC0-24,SS) within ±20% of the adult geometric mean AUC0-24,SS. Different scenarios were compared to optimise the design of the trial. To show the potential of this framework for similar compounds, the current simulation method was also evaluated with adult and paediatric data from literature on sunitinib.
CONCLUSION
The performance of PK-based clinical trials in paediatrics can be predicted and optimised through PK modelling and simulation. Application of this approach enables clinical trials in paediatrics to be performed as efficiently as possible while protecting the child from unnecessary harm.
RESULTS
At the starting dose of 300 mg/m2, the power of the trial design was 66.9%. Power did not improve by dose escalation to 350 mg/m2 (65.3%). Power increased to 78.9% with inclusion of 10 patients per trial. Paediatric sunitinib PK data were adequately predicted from adult data with a mean prediction error of 1.80%.
INTRODUCTION
Paediatric dose-finding studies are challenging to perform due to ethical reasons, the limited number of available patients and restricted number of blood samples. In certain cases, the adult pharmacokinetic (PK) exposure can be used as target for dose finding in paediatrics. The aim of this study was to investigate the performance of a paediatric phase I dose-finding clinical trial in silico.