Human total clearance values and volumes of distribution of typical human cytochrome P450 2C9/19 substrates predicted by single-species allometric scaling using pharmacokinetic data sets from common marmosets genotyped for P450 2C19

Abstract

1. Common marmosets (Callithrix jacchus) are small non-human primates that genetically lack cytochrome P450 2C9 (CYP2C9). Polymorphic marmoset CYP2C19 compensates by mediating oxidations of typical human CYP2C9/19 substrates.

2. Twenty-four probe substrates were intravenously administered in combinations to marmosets assigned to extensive or poor metaboliser (PM) groups by CYP2C19 genotyping. Eliminations from plasma of cilomilast, phenytoin, repaglinide, tolbutamide, and S-warfarin in the CYP2C19 PM group were significantly slow; these drugs are known substrates of human CYP2C8/9/19.

3. Human total clearance values and volumes of distribution of the 24 test compounds were extrapolated using single-species allometric scaling with experimental data from marmosets and found to be mostly comparable with the reported values.

4. Human total clearance values and volumes of distribution of 15 of the 24 test compounds similarly extrapolated using reported data sets from cynomolgus or rhesus monkeys were comparable to the present predicted results, especially to those based on data from PM marmosets.

5. These results suggest that single-species allometric scaling using marmosets, being small, has advantages over multiple-species-based allometry and could be applicable for pharmacokinetic predictions at the discovery stage of drug development.

Keywords:

• Allometry
• CYP2C substrate
• distribution volume
• metabolic clearance
• prediction

Acknowledgements

The authors thank Drs. Erika Sasaki and Masafumi Yamamoto of the Central Institute for Experimental Animals for providing and genotyping the marmosets. The authors also greatly thank David Smallbones for copyediting a draft of this article.

Disclosure statement

HK, HI, SM, MH, and MN are employees of CLEA Japan, Inc., the contract research organisation and breeder of common marmosets. The other authors have no interests to declare.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED [Grant 19am0101121j0003].