ADME Optimization and Toxicity Assessment in Early- and Late-Phase Drug Discovery

Abstract

Integrating physicochemical, drug metabolism, pharmacokinetics, ADME, and toxicity assays into drug discovery in order to reduce the attrition rates in clinical development is reviewed. The review is organized around three main decision points used in discovery including hit generation, lead optimization and final candidate selection stages. The preclinical strategies used at each decision point are discussed from a drug discovery perspective. Typically, preclinical data produced at these stages use lower throughput assays, smaller amounts of compounds and operate within a timeframe that is consistent with the iterative cycle of most drug discovery research projects. Understanding the false positive rates of these drug discovery preclinical assays is a must in reducing attrition rates in development.

In Silico Prediction of Caco‐2 Cell Permeability by a Classification QSAR Approach

“…[1][2][3] One of the most important challenges facing an oral drug is its movement across the intestinal epithelial barrier that determines the rate and extent of human absorption and ultimately affects its bioavailability. In addition, the permeability property per se is a multifactorial process which separates into different mechanisms, like paracellular and transcellular passive diffusion, active uptake and active secretion.…”

“…Particularly, the Caco-2 monolayer cell culture model is the "gold standard" for drug permeability and is widely used in drug discovery for the prediction of human intestinal permeability. [3] As a matter of fact, this in vitro model has been recommended by the US Food and Drug Administration (FDA) for determination of permeability of compounds to be classified according to the Biopharmaceutics Classification System (BCS). [10] Nowadays, as the number of compounds that can be generated has increased dramatically, the in vitro methods can not longer match the demand in throughput.…”

Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods

“…Given these huge expenditures, substantial savings can accrue from early recognition of problems that would alert to a compound's potential to cause adverse effects leading to attrition (Caldwell et al, 2009;Kola and Landis, 2004). The costs associated with withdrawing a drug from the market after approval are even greater.…”

Open Source Drug Discovery with Bioclipse

“…We believe that the combination of models running on the local computer with optional remote services in a graphical workbench gives a very flexible workbench for predictive toxicology. ADME predictions ADME (absorption, distribution, metabolism, and excretion) describes the disposition of a drug within an organism, and is well recognized as an important element in small molecule drug discovery and development [50]. Of primary aim in ADME modeling is to promote candidates presenting ADME-properties within certain intervals, such as the well known (but debated) Lipinski rule of having an octanol-water partition coefficient (logP) of less than 5 [51].…”