Quantitative prediction of the extent of drug–drug interaction using a physiologically based pharmacokinetic model that includes inhibition of drug metabolism determined in cryopreserved hepatocytes

Abstract

1. A physiologically based pharmacokinetic (PBPK) model that includes inhibition constant evaluated in cryopreserved hepatocytes was used to predict drug–drug interactions (DDIs) between orally administered nifedipine, a CYP substrate, and fluconazole or ketoconazole, CYP inhibitors, in rats.

2. The Kp,uu, ratio of unbound inhibitor concentration in liver ([I]liver,u) to that in plasma ([I]sys,u), of fluconazole and ketoconazole was 1.0 and 13.0, indicating that ketoconazole accumulates in liver. The ratios of inhibition constants in rat liver microsomes (Ki,mic,u) to that in rat cryopreserved hepatocytes (Ki,hep,u) for fluconazole and ketoconazole were 1.5 and 25.5, which were similar to the Kp,uu and suggested that cryopreserved hepatocytes could mimic the hepatic accumulation of inhibitors.

3. The increases in AUC of nifedipine predicted by the minimal PBPK model using [I]liver,u/Ki,mic,u and [I]sys,u/Ki,hep,u were within 1.5-fold of the observed values for both inhibitors, whereas the model using [I]sys,u/Ki,mic,u underestimated the AUC increase caused by ketoconazole 21-fold.

4. These results indicated that hepatic accumulation factor of an inhibitor is required for a precise DDI projection and that cryopreserved hepatocytes would be useful to obtain the Ki including hepatic accumulation factor. It was demonstrated that PBPK model using Ki,hep,u could be a valuable approach for quantitative DDI projection.

Keywords:

• Cryopreserved hepatocytes
• drug–drug interaction
• fluconazole
• ketoconazole
• Ki
• nifedipine
• physiologically based pharmacokinetic model

Acknowledgements

The authors thank Miyuki Funami and Teruki Hamada for many thoughtful suggestions.

Declaration of interest

The authors report no conflicts of interest.

Funding

The authors report no funding supports for this work.

Supplementary material available online