Strategy of utilizing in vitro and in vivo ADME tools for lead optimization and drug candidate selection.
The high-throughput screening in drug discovery for absorption, distribution, metabolism and excretion (ADME) properties has become the norm in the industry. Only a few years ago it was ADME properties that were attributed to more failure of drugs than efficacy or safety in the clinic trials. With the realization of new techniques and refinement of existing techniques better projections for the pharmacokinetic properties of compounds in humans are being made, shifting the drug failure attributes more to the safety and efficacy properties of drug candidates. There are a tremendous number of tools available to discovery scientists to screen compounds for optimization of ADME properties and selection of better candidates. However, the use of these tools has generally been to characterize these compounds rather than to select among them. This report discusses applications of the available ADME tools to better understand the clinical implication of these properties, and to optimize these properties. It also provides tracts for timing of studies with respect to the stage of the compound during discovery, by means of a discovery assay by stage (DABS) paradigm. The DABS provide the team with a rationale for the types of studies to be done during hit-to-lead, early and late lead optimization stages of discovery, as well as outlining the deliverables (objectives) at those stages. DABS has proven to be optimal for efficient utilization of resources and helped the discovery team to track the progress of compounds and projects.
Balani
Suresh K
SK
Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Miwa
Gerald T
GT
Gan
Liang-Shang
LS
Wu
Jing-Tao
JT
Lee
Frank W
FW
D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004345:Drug Industry / Q000379:methods; D008722:Methods; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics
D004364:Pharmaceutical Preparations