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

• Type of Material: Article
• Authors: Daniel M Naagaard, Swarthmore College; Roy Chang, Emory University; Mats Någård, AstraZeneca; Weifeng Tang, AstraZeneca; David W Boulton, AstraZeneca
• Language: English
• Date: 2022-02-01
• Publisher: Emory University Libraries
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/bcp.15117
• Title of Journal or Parent Work: British Journal of Clinical Pharmacology
• Volume: 88
• Issue: 4
• Start Page: 1942
• End Page: 1946
• Grant/Funding Information: AstraZeneca
• Keywords: UGT1A9; Glucuronosyltransferase; polymorphism; Benzhydryl Compounds; dapagliflozin; type 2 diabetes mellitus; UDP-Glucuronosyltransferase 1A9; Glucosides; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Humans; Sodium-Glucose Transporter 2 Inhibitors; oral clearance
• Research Categories: Health Sciences, Pharmacology

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.