Key result
In vitro microsomal stability testing correlates only moderately with in vivo clearance, questioning early triage utility.
Why the study?
Putative in vitro-in vivo correlations of pharmacokinetic parameters are regarded as a prerequisite to filter hits from high-throughput screening for subsequent in vivo PK studies, but their validity is uncertain.
Effect estimate: r^2 0.31 (rat) and 0.27 (human)
Microsomal stability testing may not be a reliable tool to triage early compounds for in vivo pharmacokinetic testing due to moderate in vitro-in vivo correlations.
Caution against relying on microsomal stability for early compound triage; leaves open the need for stronger predictive pharmacokinetic models.
BACKGROUND/AIMS: Putative in vitro-in vivo correlations of pharmacokinetic (PK) parameters are regarded as a prerequisite to filter hits derived from high-throughput screening (HTS) approaches for subsequent murine in vivo PK studies. METHODS: In this study, we assessed stabilities in rat and human microsomes of 121 compounds from an early, academic drug discovery programme targeting the (pro)renin receptor and correlated the respective data with single-dose, in vivo PK parameters of 22 hits administered intravenously in rats. RESULTS: After transformation of in vitro half-lives to predicted in vivo hepatic clearances, r(2) regarding in vitro-in vivo clearance correlations were 0.31 and 0.27 for the rat and human species, respectively. CONCLUSIONS: Our data concerning structurally diverse real-world compounds indicate that microsomal stability testing is not a tool to triage early compounds for in vivo PK testing.
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Schrezenmeier et al. (2012) studied Drug discovery targeting the (pro)renin receptor. In vitro microsomal stability testing vs. In vivo pharmacokinetic testing was evaluated on In vitro-in vivo clearance correlation (r^2) (r^2 0.31 (rat) and 0.27 (human)). In vitro microsomal stability testing showed only moderate correlation with in vivo hepatic clearance (r^2 0.31 for rat, 0.27 for human), questioning its utility for triaging early compounds.
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