From Kidney and Liver Interaction in Patients with CKD to the Drug-Drug-Severe CKD Disease Interaction Predicted by PBPK

Chronic kidney disease (CKD) is more than renal malfunction alone. It may affect drug disposition by multiple pathophysiological changes including the changes in abundancy and activity of hepatic drug transporters. Also, the disease factors may interplay with drug-drug interaction (DDI) in patients with CKD causing a different DDI scenario from the one in healthy volunteers. The translation of DDI magnitude between healthy subjects and patients with CKD may not be straightforward due to the complex drug-drug-disease interaction (DDDI) scenarios, whereas physiologically based pharmacokinetic (PBPK) model-based approach may serve as a valuable quantitative tool to predict the complex DDDI. Herein, we illustrate how to use PBPK modelling to predict the DDI between statins and roxadustat mediated by hepatic transporters in patients with severe CKD, and answer the following questions: how much does severe CKD affect the abundancy and activity of hepatic transporters? Which pathways(s) are the major one(s) responsible for the observed alteration of statins PK in patients with severe CKD? Is the magnitude of statin-roxadustat DDI in severe CKD patients similar to that in HV? What are the optimal dose regimens when statins and roxadustat are co-administered in patients with severe CKD?