Human plasma concentrations of five cytochrome P450 probes extrapolated from pharmacokinetics in dogs and minipigs using physiologically based pharmacokinetic modeling

Abstract

1. The pharmacokinetics of cytochrome P450 probes in humans can be extrapolated from corresponding data in cynomolgus monkeys using simplified physiologically based pharmacokinetic (PBPK) modeling. In the current study, despite some species difference in drug clearances, this modeling methodology was adapted to estimate human plasma concentrations of P450 probes based on data from commonly used medium-sized experimental animals, namely dogs and minipigs.

2. Using known species allometric scaling factors and in vitro metabolic clearance data, the observed plasma concentrations of slowly eliminated caffeine and warfarin and rapidly eliminated omeprazole, metoprolol and midazolam in two young dogs were scaled to human oral monitoring equivalents. Using the same approach, the previously reported pharmacokinetics of the five P450 probes in minipigs was also scaled to human monitoring equivalents.

3. The human plasma concentration profiles of the five P450 probes estimated by the simplified human PBPK models based on observed/reported pharmacokinetics in dogs/minipigs were consistent with previously published pharmacokinetic data in humans.

4. These results suggest that dogs and minipigs, in addition to monkeys, could be suitable models for humans during research into new drugs, especially when used in combination with simple PBPK models.

• Hepatic clearance
• PBPK modeling
• P450 substrates

Acknowledgements

We would like to thank Drs. Yoshiyuki Yamaura, Kenich Nunoya, Takashi Koyanagi, Masayuki Mogi, Ryohji Takano, Sayako Nishiyama, Norie Murayama and Makiko Shimizu 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 (H.Y.). The authors state that there are no other declarations of interest. The authors are responsible for the content and writing of the article.