Challenges and considerations for development of therapeutic proteins in pediatric patients.

Target specificity and generally good tolerability of therapeutic proteins (TPs) present desirable treatment opportunities for pediatric patients. However, little is known on the ontogeny of processes related to the pharmacokinetics (PK) and disposition of TPs. The science, regulatory requirements and strategy of developing TPs for children are evolving. Our current review of TPs, (with focus on monoclonal antibodies and fusion proteins) that were approved for pediatric use indicates that dose-selection for pediatric pivotal studies is often based on adult PK information alone. This approach might not be sufficient if more complex PK properties than simple linear PK are present. Body weight-based dosing for pediatric patients directly scaled down from adult dosing can lead to under-exposure in young pediatric patients who are usually in the lowest body-weight range. Tiered-fixed dosing can be reasonably effective for TPs in achieving comparable exposure in children over a wide age range. The uniqueness of the pediatric population, the practical challenges in conducting clinical studies in this population, as well as regulations from health authorities warrant including pharmacometrics as an integral component of pediatric drug development. We propose a framework distinct from previous proposals, to guide clinical pharmacology strategy for pediatric drug development specifically for TPs.