Knowledge-driven approaches for the guidance of first-in-children dosing.

Pediatric pharmacokinetic and pediatric safety and efficacy studies are, in most cases, a mandatory activity during the drug development process in North America and Europe. Pharmacokinetic modeling in anticipation of the pediatric clinical trial should take a data or knowledge-driven approach by employing either top-down or bottom-up approaches to assessing differential age-related dosing. These two approaches depend on different starting information and are likely to be used in conjunction with each other for the purposes of defining pediatric dosing guidelines. This review primarily focuses on the available bottom-up, mechanistic models for predicting age-dependent drug absorption, distribution and elimination, and their integration through the whole-body physiologically based pharmacokinetic (PBPK) model. The bottom-up approach incorporating adult and pediatric whole-body PBPK models for optimizing age-related dosing is detailed for a drug currently undergoing pediatric development.