Moderate Correlations of in vitro versus in vivo Pharmacokinetics Questioning the Need of Early Microsomal Stability Testing

Abstract

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, r² 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.

Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability

“…Interestingly, 107 ( GNE7599 ) has a 4-fold lower plasma clearance (13.9 mL/min/kg for 107 ( GNE7599 ) vs 57.7 mL/min/kg for VH-021) , while the volume of distribution ( V ss ) was relatively unchanged, as well as the plasma half-life (<2-fold). The reason for the lower in vivo clearance of 107 ( GNE7599 ) compared to VH-021 is currently unknown, but it might be attributed to its higher plasma protein binding potential, which has been implicated in limiting access to the hepatic compartment and thus providing protection from metabolism . Most strikingly, the oral bioavailability of 107 ( GNE7599 ), F = 46.5%, was dramatically improved, resulting in a ∼17-fold enhancement compared to VH-021 ( F = 2.7%).…”

“…The reason for the lower in vivo clearance of 107 (GNE7599) compared to VH-021 is currently unknown, but it might be attributed to its higher plasma protein binding potential, which has been implicated in limiting access to the hepatic compartment and thus providing protection from metabolism. 42 Most strikingly, the oral bioavailability of 107 (GNE7599), F = 46.5%, was dramatically improved, resulting in a ∼17-fold enhancement compared to VH-021 (F = 2.7%). This significant improvement in the oral bioavailability of 107 (GNE7599) is based mainly on the increased absorption of the compound (high F a ) and is also consistent with better cell permeability in MDCK assays (Table 7).…”

Biological Activity and Stability of Aeruginosamides from Cyanobacteria

“…It did not affect T47D, and its stability in the S9 assay was significantly lower. The results of the in vitro assay may have low correlation with the in vivo behaviour of aeruginosamides, as revealed in the case of other compounds [57]. Nonetheless, in conjunction with findings from other analyses, they can provide an important indication about the peptides as possible lead molecules in drug development.…”