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Common UGT1A9 polymorphisms do not have a clinically meaningful impact on the apparent oral clearance of dapagliflozin in type 2 diabetes mellitus
Author(s) -
Naagaard M. Daniel,
Chang Roy,
Någård Mats,
Tang Weifeng,
Boulton David W.
Publication year - 2022
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.15117
Subject(s) - dapagliflozin , medicine , diabetes mellitus , type 2 diabetes mellitus , type 2 diabetes , benzhydryl compounds , endocrinology , chemistry , organic chemistry , bisphenol a , epoxy
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.