Distinguishing between the Permeability Relationships with Absorption and Metabolism To Improve BCS and BDDCS Predictions in Early Drug Discovery

Abstract

The biopharmaceutics classification system (BCS) and biopharmaceutics drug distribution classification system (BDDCS) are complementary classification systems that can improve, simplify, and accelerate drug discovery, development, and regulatory processes. Drug permeability has been widely accepted as a screening tool for determining intestinal absorption via the BCS during the drug development and regulatory approval processes. Currently, predicting clinically significant drug interactions during drug development is a known challenge for industry and regulatory agencies. The BDDCS, a modification of BCS that utilizes drug metabolism instead of intestinal permeability, predicts drug disposition and potential drug–drug interactions in the intestine, the liver, and most recently the brain. Although correlations between BCS and BDDCS have been observed with drug permeability rates, discrepancies have been noted in drug classifications between the two systems utilizing different permeability models, which are accepted as surrogate models for demonstrating human intestinal permeability by the FDA. Here, we recommend the most applicable permeability models for improving the prediction of BCS and BDDCS classifications. We demonstrate that the passive transcellular permeability rate, characterized by means of permeability models that are deficient in transporter expression and paracellular junctions (e.g., PAMPA and Caco-2), will most accurately predict BDDCS metabolism. These systems will inaccurately predict BCS classifications for drugs that particularly are substrates of highly expressed intestinal transporters. Moreover, in this latter case, a system more representative of complete human intestinal permeability is needed to accurately predict BCS absorption.

The utility of in vitro trials that use Caco-2 cell systems as a replacement for animal intestinal permeability and human bioequivalence measurements in drug development

“…Although in Caco-2 cell model transporter effects may emerge from endogenously expressed proteins [8] , it has been suggested to limit the application of Caco-2 permeability screening to passive compounds. However, the majority of drugs on the market include both passive diffusion and active transport [9] . In this study, we focus on the Caco-2 endogenous cell system and evaluate its utility and adequacy in assessing the P-gp mediated efflux.…”

“…Embora nas cé-lulas Caco-2 os efeitos dos transportadores possam surgir devido a proteínas expressas endogenamente [8] tem sido sugerido limitar o rastreio da permeabilidade em Caco-2 a compostos com absorção maioritária por difusão passiva. No entanto, a generalidade dos fármacos no mercado incluem componentes tanto de difusão passiva como de transporte ativo [9] . Neste estudo focamo--nos no sistema celular endógeno das células Caco-2 e avaliamos a sua utilidade na avaliação do efluxo mediado pela P-gp.…”

A Novel Approach in Distinguishing Between Role of Hydrodynamics and Mechanical Stresses Similar to Contraction Forces of GI Tract on Drug Release from Modified Release Dosage Forms

“…Many new chemical entities (NCEs) fail during early drug development phases because of undesirable toxicity and/or lack of efficacy instigated by poor solubility, permeability, and bioavailability (1). It is indispensable to have a strategy by which properties of such drug candidates can be accurately and predictively identified in the early stages of drug development phases.…”

Oral delivery strategies for nutraceuticals: Delivery vehicles and absorption enhancers

“…The recently developed biopharmaceutics drug 224 disposition classification system (BDDCS) factors in drug metabolism by Phase I and II 225 processes and is useful in predicting drug-drug interactions that may occur in the intestine 226 and liver (Larregieu & Benet, 2014). Enzymatic metabolism is particularly relevant to fatty 227 acids and peptides which are targeted by lipases and peptidases respectively.…”

“…Transport via the paracellular route requires movement 258 through tight junctions. A molecular radius between 10-50 Å and molecular weight <500 Da 259 is required and the bioactive must be hydrophilic in nature (Larregieu & Benet, 2014). 260…”