Probe ADME and Test Hypotheses: A PATH beyond clearance in vitro-in vivo correlations in early drug discovery
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Bell, Leslie and Wang, Jianling (2012) Probe ADME and Test Hypotheses: A PATH beyond clearance in vitro-in vivo correlations in early drug discovery. Expert Opintion on Drug Metabolism and Toxicology. ISSN 1742-5255
Abstract
Introduction: In vitro metabolic profiling is used extensively by the pharmaceutical industry to characterize and optimize oral drug properties. With heavy emphasis on modeling hepatic metabolism, the in vivo clearance of half of all new chemical entities remains poorly predicted, based on rat pharmacokinetic data in Novartis. The common route to illuminating key drivers of in vivo clearance beyond hepatic metabolism is, frequently, process of elimination, a time-consuming and sometimes resource-intensive practice. Leveraging profiling strategies that incorporate physicochemical trends and integrate diverse cues gathered from ADME in vitro and in vivo assays should enable more nimble and efficient diagnosis of drug clearance.
Areas covered: This article reviews aspects of early in vitro-in vivo clearance correlation (IVIVC) analysis. This includes relevant in silico advances and in vitro opportunities for clearance characterization and data trend analysis. Optimization of in vitro-in silico strategies for mitigating specific metabolic liabilities is discussed. Potential reasons for under- and over-estimation of in vivo clearance, obtained from in vitro approaches, are reviewed. Integrating these observations, 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.
Expert opinion: Since hepatic cytochrome P450 (CYP450) metabolism seems to represent the rate-limiting metabolic step to in vivo clearance for the majority of drug candidates, in vitro stability measurements and conventional scaling from microsomal CYP450 models remain the most practical way to triage for high metabolic liabilities, though routinely scaled measurements of CYP450 activity accurately predict in vivo clearance for ~45% of discovery compounds. Clearance is a complex process involving multiple mechanisms and even correction by 1-2 parameters may not sufficiently address the disconnection for all. While protein binding is used semi-routinely to adapt IVIVC, many other factors tend to be overlooked in correlation analyses. Consideration of intrinsic permeability and ionization at physiologic pH may yield insight into distribution-limited clearance. As well, attention to hydrophobic character and demonstration of transporter interaction can be valuable in diagnosing dominant clearance pathways. Within a project, proper dissection of scaffold-specific in vitro-in vivo disconnects lending to apparent IVIV trends may be needed to identify meaningful clearance structure-property relationships (SPR). An integrated-ADME approach to clearance interrogation is expected to help refine the in vitro-in silico strategies that guide medicinal chemistry.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Restrictions: 12 month embargo for STM, Behavioural Science and Public Health Journals 18 month embargo for SSH journals |
| Keywords: | ADME, IVIVC, CYP450, metabolism, mechanism of clearance |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/7290 |