Summary of the National Institute of Child Health and Human Development-best pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics Classification System Working Group

Background: The Biopharmaceutics Classification System (BCS) allows compounds to be classified based on their in vitro solubility and intestinal permeability. The BCS has found widespread use in the pharmaceutical community to be an enabling guide for the rational selection of compounds, formulation for clinical advancement, and generic biowaivers. The Pediatric Biopharmaceutics Classification System (PBCS) Working Group was convened to consider the possibility of developing an analogous pediatric-based classification system. Because there are distinct developmental differences that can alter intestinal contents, volumes, permeability, and potentially biorelevant solubilities at different ages, the PBCS Working Group focused on identifying age-specific issues that need to be considered in establishing a flexible, yet rigorous PBCS.

Objective: We summarized the findings of the PBCS Working Group and provided insights into considerations required for the development of a PBCS.

Methods: Through several meetings conducted both at The Eunice Kennedy Shriver National Institute of Child Health, Human Development-US Pediatric Formulation Initiative Workshop (November 2011) and via teleconferences, the PBCS Working Group considered several high-level questions that were raised to frame the classification system. In addition, the PBCS Working Group identified a number of knowledge gaps that need to be addressed to develop a rigorous PBCS.

Results: It was determined that for a PBCS to be truly meaningful, it needs to be broken down into several different age groups that account for developmental changes in intestinal permeability, luminal contents, and gastrointestinal (GI) transit. Several critical knowledge gaps were identified, including (1) a lack of fully understanding the ontogeny of drug metabolizing enzymes and transporters along the GI tract, in the liver, and in the kidney; (2) an incomplete understanding of age-based changes in the GI, liver, and kidney physiology; (3) a clear need to better understand age-based intestinal permeability and fraction absorbed required to develop the PBCS; (4) a clear need for the development and organization of pediatric tissue biobanks to serve as a source for ontogenic research; and (5) a lack of literature published in age-based pediatric pharmacokinetics to build physiologically- and population-based pharmacokinetic (PBPK) databases.

Conclusions: To begin the process of establishing a PBPK model, 10 pediatric therapeutic agents were selected (based on their adult BCS classifications). These agents should be targeted for additional research in the future. The PBCS Working Group also identified several areas where greater emphasis on research was needed to enable the development of a PBCS.