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

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. © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Citation

M Daniel Naagaard, Roy Chang, Mats Någård, Weifeng Tang, David W Boulton. Common UGT1A9 polymorphisms do not have a clinically meaningful impact on the apparent oral clearance of dapagliflozin in type 2 diabetes mellitus. British journal of clinical pharmacology. 2022 Feb;88(4):1942-1946

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PMID: 34687551

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