Formulation Strategy of BCS-II Drugs by Coupling Mechanistic In-Vitro and Nonclinical In-Vivo Data with PBPK: Fundamentals of Absorption-Dissolution to Parameterization of Modelling and Simulation

Abstract

BCS class II candidates pose challenges in drug development due to their low solubility and permeability. Researchers have explored various techniques; co-amorphous and solid dispersion are major approaches to enhance in-vitro drug solubility and dissolution. However, in-vivo oral bioavailability remains challenging. Physiologically based pharmacokinetic (PBPK) modeling with a detailed understanding of drug absorption, distribution, metabolism, and excretion (ADME) using a mechanistic approach is emerging. This review summarizes the fundamentals of the PBPK, dissolution—absorption models, parameterization of oral absorption for BCS class II drugs, and provides information about newly emerging artificial intelligence/machine learning (AI/ML) linked PBPK approaches with their advantages, disadvantages, challenges and areas of further exploration. Additionally, the fully integrated workflow for formulation design for investigational new drugs (INDs) and virtual bioequivalence for generic molecules falling under BCS-II are discussed.

Graphical Abstract