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

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.