Human plasma concentrations of cytochrome P450 probe cocktails extrapolated from pharmacokinetics in mice transplanted with human hepatocytes and from pharmacokinetics in common marmosets using physiologically based pharmacokinetic modeling

Abstract

1. The pharmacokinetic data of cytochrome P450 probes in humans can be extrapolated from corresponding data in cynomolgus monkeys, dogs and minipigs using simplified physiologically based pharmacokinetic (PBPK) modeling. In this study, the modeling methodology was further adapted to estimate human plasma concentrations of P450 probes based on data from mice transplanted with human hepatocytes or based on data from marmosets.

2. Using known species allometric scaling factors, the observed plasma concentrations of caffeine, warfarin, omeprazole, metoprolol, and midazolam in chimeric TK-NOG mice with humanized liver were scaled to human oral monitoring equivalents. Using the same approach, the previously reported pharmacokinetics of the five P450 probes in marmosets were also scaled to reported equivalents in humans using in vitro metabolic clearance data.

3. Human plasma concentration profiles of the five P450 probes estimated by simplified human PBPK models based on the observed pharmacokinetics in mice with humanized liver and on the reported pharmacokinetics in marmosets were consistent with previously published pharmacokinetic data in Caucasians.

4. These results suggest that mice with humanized liver and/or marmosets could be suitable pharmacokinetic models for humans during research into new drugs, especially when used in combination with simple PBPK models.

Keywords:

• Hepatic clearance
• P450 substrates
• PBPK modeling

Acknowledgments

We would like to thank Drs. Miyuki Kuronuma, Takashi Inoue, Masayuki Mogi and Norie Murayama for their support of this study and David Smallbones for his English advice.

Declaration of interest

This work was supported in part by JCIA’s LRI program and by a Grant-in-Aid for Scientific Research and was also part of the Construction of System for Spread of Primate Model Animals under the Strategic Research Program for Brain Sciences of the Japan Agency for Medical Research and Development. The authors state that there are no other interests to declare. The authors alone are responsible for the content and writing of the article.