Probe ADME and test hypotheses: a PATH beyond clearance in vitro-in vivo correlations in early drug discovery.
BACKGROUND
In vitro cytochrome P450 (CYP450) metabolic profiling is pursued extensively to optimize drug properties. Still, the in vivo clearance of half of all new chemical entities (NCEs) remains poorly predicted by CYP450 metabolism, based on Novartis rat pharmacokinetic data. The conventional route to illuminating key drivers of in vivo clearance beyond hepatic metabolism is, frequently, the process of elimination, a time-consuming and sometimes resource-intensive practice. A more nimble and efficient diagnosis of drug clearance is imperative to support today's chemistry optimization.


METHODS
This article reviews in vitro-in vivo clearance correlation (IVIVC) analysis of drugs and NCEs including in silico advances, in vitro opportunities for clearance characterization and guidance for proper interpretation of clearance data. Potential mechanisms for under- and overestimation of in vivo clearance obtained from in vitro approaches are reviewed. The article offers insight into a practical PATH (Probe ADME and Test Hypotheses) for discovery data analysis that can enrich IVIVC development and guide more efficient use of the ADME-PK toolbox.


CONCLUSIONS
In vitro hepatic CYP450 stability measurements remain the most practical way to triage for high metabolic liabilities. Clearance is a complex process involving multiple mechanisms and many factors tend to be overlooked in routine correlation analyses. Equilibrium protein binding, intrinsic permeability and ionization may yield insight into distribution-limited clearance. In addition, hydrophobic character and transporter interaction can be valuable in diagnosing dominant clearance pathways. An integrated ADME approach to clearance interrogation is expected to help refine the in vitro-in silico strategies that guide medicinal chemistry.
Novartis Institutes for Biomedical Research, Metabolism and Pharmacokinetics, Cambridge, MA 02139, USA. leslie.bell@novartis.com
Leslie C
LC
Bell
Jianling
J
Wang
D000818:Animals; D019295:Computational Biology; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis* / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010599:Pharmacokinetics; D011485:Protein Binding
D003577:Cytochrome P-450 Enzyme System