Clinical trial simulations to optimize dose finding studies in paediatric oncology
Julie M. Janssen (1), C. Michel Zwaan (2), Jan H.M. Schellens (3, 4), Jos H. Beijnen (1, 4), Alwin D.R. Huitema (1, 5)
(1) Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek, Amsterdam, The Netherlands, (2) Department of Pediatric Oncology/Hematology, Erasmus-MC Sophia Children’s Hospital, Rotterdam, The Netherlands, (3) Department of Clinical Pharmacology, Antoni van Leeuwenhoek, Amsterdam, The Netherlands, (4) Science Faculty, Utrecht University for Pharmaceutical Sciences (UIPS), Utrecht, The Netherlands, (5) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
Objectives: Paediatric dose finding studies are challenging to perform due to ethical reasons, the limited number of available patients and the restricted number of blood samples. In certain cases, the adult exposure can be used as target for dose finding in paediatrics. A paediatric phase I dose finding clinical trial, targeting the observed adult area under the plasma concentration-time curve at steady-state (AUC24,SS), has been designed for the anticancer drug bosutinib (study ITCC054). In this ITCC trial, the approved adult dose scaled based on body surface area is to be given to a small number of children to show similar pharmacokinetic (PK) exposure and safety. The aim of this study was to investigate the power of this design to show similar PK exposure as observed in adults.
Methods: Paediatric PK parameters were extrapolated from adult values by allometric scaling [1, 2]. Based on the scaled parameters, individual simulated body weights and doses, individual paediatric PK curves were simulated. Subsequently, a clinical trial simulation was performed to determine the power of the proposed trial design, consisting of 6 paediatric patients and 6 sample time points (pre-dose and 1, 3, 6, 8, 24 hours post-dose). Power was defined as the fraction of 1000 trials with a geometric mean AUC24,SS within the target range (±20% of the adult geometric mean AUC24,SS, i.e. 3640 h*ng/mL). Different sampling schedules were compared in additional simulations to optimize the trial design.
Results: At the starting dose of 300 mg/m2 (equivalent to the approved 500 mg dose in adults), the power of the trial design was 66.9%. The exposure on this dose level was 3442 h*ng/mL. Power did not improve by increasing the dose to 350 mg/m2, the next higher predefined dose level (65.3%). Addition of one sample resulted in similar results as the original sample schedule (67.5% and 67.7% versus 66.9%). Removal of one sample in the absorption and elimination phase of the curve did not substantially decrease the power (64.8% and 57.9% versus 66.9%). Increasing the number of patients to 10 patients per trial resulted in an increased power of 78.9%. Increasing the sample size to 10 patients is currently being considered.
Conclusions: The power of PK analysis in paediatric clinical trials can be predicted and optimized through PK simulations. This enables clinical trials in paediatrics to be performed as efficient as possible while protecting the child from unnecessary harm.
References:
[1] Hsyu P, Mould DR, Abbas R, Amantea M. Population Pharmacokinetic and Pharmacodynamic Analysis of Bosutinib. Drug Metab Pharmacokinet. 2014;29(6):441-8.
[2] Anderson BJ, Holford NHG. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303-32.
