Challenging the Relevance of Unbound Tissue-to-Blood Partition Coefficient ( Kp _uu ) on Prediction of Drug-Drug Interactions

Abstract

Purpose:

To examine the theoretical/practical utility of the liver-to-blood partition coefficient ( Kp _uu ) for predicting drug-drug interactions (DDIs), and compare the Kp _uu -approach to the extended clearance concept AUC _R -approach.

Methods:

The Kp _uu relationship was derived from first principles. Theoretical simulations investigated the impact of changes in a single hepatic-disposition process on unbound systemic ( AUC _B,u ) and hepatic exposure ( AUC _H,u ) versus Kp _uu . Practical aspects regarding Kp _uu utilization were examined by predicting the magnitude of DDI between ketoconazole and midazolam employing published ketoconazole Kp _uu values.

Results:

The Kp _uu hepatic-disposition relationship is based on the well-stirred model. Simulations emphasize that changes in influx/efflux intrinsic clearances result in Kp _uu changes, however AUC _H,u remains unchanged. Although incorporation of Kp _uu is believed to improve DDI-predictions, utilizing published ketoconazole Kp _uu values resulted in prediction errors for a midazolam DDI.

Conclusions:

There is limited benefit in using Kp _uu for DDI-predictions as the AUC _R -based approach can reasonably predict DDIs without measurement of intracellular drug concentrations, a difficult task hindered by experimental variability. Further, Kp _uu changes can mislead as they may not correlate with changes in AUC _B,u or AUC _H,u . The well-stirred model basis of Kp _uu when applied to hepatic-disposition implies that nuances of intracellular drug distribution are not considered by the Kp _uu model.