Common UGT1A9 polymorphisms do not have a clinically meaningful impact on the apparent oral clearance of dapagliflozin in type 2 diabetes mellitus

• Authors: Daniel M Naagaard, Swarthmore College; Roy Chang, Emory University; Mats Någård, AstraZeneca; Weifeng Tang, AstraZeneca; David W Boulton, AstraZeneca
• Journal Title: British Journal of Clinical Pharmacology
• Volume: Volume 88, Number 4
• Publisher: (publisher) | 2022-02-01, Pages 1942-1946
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1111/bcp.15117
• Subjects: Health Sciences, Pharmacology
• Keywords: UGT1A9; dapagliflozin; oral clearance; polymorphism; type 2 diabetes mellitus; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Glucosides; Glucuronosyltransferase; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors; UDP-Glucuronosyltransferase 1A9

Abstract

Dapagliflozin is an inhibitor of human renal sodium-glucose cotransporter 2 (SGLT2), first approved for the treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin is primarily metabolized by uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9). The effect of UGT1A9 polymorphisms on dapagliflozin apparent oral clearance (CL/F) was studied with dapagliflozin population pharmacokinetic data and UGT1A9 genotype data (I.399C>T, rs2011404, rs6759892, rs7577677, rs4148323, UGT1A9*2 and UGT1A9*3) from a Phase 2 study conducted in subjects with T2DM (n = 187). An analysis of covariance (ANCOVA) model accounting for known covariates influencing dapagliflozin CL/F was applied to these data to quantify the impact of each UGT1A9 polymorphism relative to the wildtype UGT1A9 genotype. The analysis showed that the geometric mean ratios of dapagliflozin CL/F for all of the UGT1A9 polymorphisms studied were within the range of wildtype UGT1A9 CL/F values. Consequently, the polymorphisms of UGT1A9 studied had no clinically meaningful impact on the CL/F of dapagliflozin.