Use of Physiologically Based Pharmacokinetic Modeling to Evaluate the Impact of Chronic Kidney Disease on CYP3A4-Mediated Metabolism of Saxagliptin.

ABSTRACT: We characterized the impact of chronic kidney disease (CKD) on the cytochrome P450 (CYP) 3A4-mediated metabolism of saxagliptin to its metabolite, 5-hydroxysaxagliptin, using a physiologically based pharmacokinetic (PBPK) model. A PBPK model of saxagliptin and its CYP3A4 metabolite, 5-hydroxysaxagliptin, was constructed and validated for oral doses ranging from 5 to 100 mg. The observed ratios of area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max ) between healthy subjects and subjects with CKD were compared with those predicted using PBPK model simulations. Simulations were performed with virtual CKD populations having decreased CYP3A4 activity (ie, 64%-75% of the healthy subjects' CYP3A4 abundance) and preserved CYP3A4 activity (ie, 100

SUBMITTER: Butrovich MA 

PROVIDER: S-EPMC9545133 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature