Abstract
Renal Impairment (RI) is a major health concern with a growing prevalence. RI leads to various physiological changes, in addition to a decrease in GFR, 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 utilize the physiologically based pharmacokinetic (PBPK) modeling platform, Simcyp® to (1) assess the impact of alterations in DT expression, toxin-drug interactions (TDIs) and free fraction (fu) on PK predictions for the OCT2/MATE1 substrate metformin in RI populations, and (2) utilize 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 on 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.
- kidney/renal
- modeling and simulation
- pharmacokinetics
- Transporter-mediated drug/metabolite disposition
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics