ADME optimization and toxicity assessment in early- and late-phase drug discovery.
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.
Caldwell
Gary W
GW
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Drug Discovery Department Welsh and McKean Roads, P.O. Box 776, Spring House, PA 19477, USA. gcaldwel@ITS.jnj.com
Yan
Zhengyin
Z
Tang
Weimin
W
Dasgupta
Malini
M
Hasting
Becki
B
D002273:Carcinogens / Q000493:pharmacokinetics; D055808:Drug Discovery; D009153:Mutagens / Q000493:pharmacokinetics; D010539:Permeability; D010599:Pharmacokinetics; D017382:Reactive Oxygen Species / Q000493:pharmacokinetics; D012995:Solubility
D002273:Carcinogens; D009153:Mutagens; D017382:Reactive Oxygen Species