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 (Cmax) 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% of the healthy subjects’ CYP3A4 abundance). We found that simulations using decreased CYP3A4 activity generally overpredicted the ratios of saxagliptin AUC and Cmax in CKD compared with those using preserved CYP3A4 activity. Similarly, simulations using decreased CYP3A4 activity underpredicted the ratio of 5‐hydroxysaxagliptin AUC in moderate and severe CKD compared with simulations using preserved CYP3A4 activity. These findings suggest that decreased CYP3A4 activity in CKD underpredicts saxagliptin clearance compared with that observed clinically. Preserving CYP3A4 activity in CKD more closely estimates saxagliptin clearance and 5‐hydroxysaxagliptin exposure changes observed in vivo. Our findings suggest that there is no clinically meaningful impact of CKD on the metabolism of saxagliptin by CYP3A4. Since saxagliptin is not a highly sensitive substrate and validated probe for CYP3A4, this work represents a case study of a CYP3A4 substrate‐metabolite pair and is not a generalization for all CYP3A4 substrates.