Prediction of the Effects of Renal Impairment on Clearance for Organic Cation Drugs that Undergo Renal Secretion: A Simulation-Based Study.

Renal impairment (RI) is a major health concern with a growing prevalence. RI leads to various physiologic changes, in addition to a decrease in glomerular filtration rate, that impact the pharmacokinetics (PK) and, specifically, the renal clearance (CLR) of compounds, including alterations of drug transporter (DT)/drug-metabolizing enzyme expression and activity, as well as protein binding. The objectives of this study were to use a physiologically based pharmacokinetic modeling platform to 1) assess the impact of alterations in DT expression, toxin-drug interactions (TDIs), and free fraction (fu) on PK predictions for the organic cation transporter 2/multidrug and toxin extrusion protein 1 substrate metformin in RI populations; and 2) use available in vitro data to improve predictions of CLR for two actively secreted substrates, metformin and ranitidine. The goal was to identify changes in parameters other than glomerular filtration rate-namely, fu and DT expression/activity-that are consistent with in vitro and clinical data in RI, and predict the importance of these parameters in the PK of metformin and ranitidine in RI patients. Our results demonstrated that including alterations in DT expression and fu, and including TDIs affecting DT activity, as indicated by in vitro data, improved the simulated predictions of CLR and other PK parameters for both metformin and ranitidine in RI. Our simulations suggest that modifications of DT expression/activity and fu are necessary for improved predictions of CLR in RI for compounds that are actively secreted, and that improvement of PK predictions in RI populations for metformin and ranitidine can be obtained by incorporating in vitro data.