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

Abstract

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 as 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. Since there are distinct developmental differences that can alter intestinal contents, volumes, permeability and potentially biorelevant solubilities at the different ages, the PBCS working group focused on identifying age specific issues that would need to be considered in establishing a flexible, yet rigorous PBCS. Objective To summarize the findings of the PBCS working group and provide insights into considerations required for the development of a pediatric based biopharmaceutics classification system. Methods Through several meetings conducted both at The Eunice Kennedy Shriver National Institute of Child Health, Human Development (NICHD)-US Pediatric Formulation Initiative (PFI) 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 would need to be addressed in order to develop a rigorous PBCS. Results It was determined that for a PBCS to be truly meaningful, it would need to be broken down into several different age groups that would account for developmental changes in intestinal permeability, luminal contents, and gastrointestinal transit. Several critical knowledge gaps where identified including: 1) a lack of fully understanding the ontogeny of drug metabolizing enzymes and transporters along the gastrointestinal (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 in order to build Physiologically- and Population-Based Pharmacokinetic (PBPK) databases. Conclusions To begin the process of establishing a PBPK model, ten pediatric therapeutic agents were selected (based on their adult BCS classifications). Those agents should be targeted for additional research in the future. The PBCS working group also identified several areas where a greater emphasis on research is needed to enable the development of a PBCS.

Considerations for a Pediatric Biopharmaceutics Classification System (BCS): Application to Five Drugs

“…The Pediatric Biopharmaceutics Classification System Working Group has outlined considerations for a possible pediatric BCS (8). Work in this present study extends findings of the Pediatric Biopharmaceutics Classification System Working Group.…”

“…It has been recognized that further research is needed to facilitate the development of a pediatric-specific BCS system (6). Of course, adult and pediatric patients differ in many aspects (7,8). For example, pediatric patients have developing and significantly different absorption, distribution, metabolism, and excretion processes, in comparison to adults (7,8).…”

“…Of course, adult and pediatric patients differ in many aspects (7,8). For example, pediatric patients have developing and significantly different absorption, distribution, metabolism, and excretion processes, in comparison to adults (7,8). These differences, along with other changes during growth and development, indicate the need for a BCS for pediatric medications.…”

Paediatric Drug Development and Formulation Design—a European Perspective

“…pharmacodynamics (PD) (21). Moreover, it must be realized that the permeability and solubility of a drug substance in children may differ from adults, meaning that the Biopharmaceutical Classification System (BCS) must be used with caution (22,23). When deciding on suitable dosing, other aspects which may have an impact on the PKPD of a drug product in an individual child must be considered as well, e.g.…”

A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms

“…This requirement needs to be factored into the overall development program for pediatric dosage forms. Recently, there has been discussion of whether the extrapolation of BCS data from adults to pediatric populations is appropriate (11). The BCS system is based on a fundamental model of the gastrointestinal tract for the estimation of the extent of absorption, taking into account important physicochemical-physiological parameters such as aqueous solubility, intestinal permeability, drug dose, volume of luminal contents, fluid flow rate, and intestinal surface area.…”