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 dapaglif...

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Published inBritish journal of clinical pharmacology Vol. 88; no. 4; pp. 1942 - 1946
Main Authors Naagaard, M. Daniel, Chang, Roy, Någård, Mats, Tang, Weifeng, Boulton, David W.
Format Journal Article
LanguageEnglish
Published England John Wiley and Sons Inc 01.02.2022
Subjects
dapagliflozin
oral clearance
polymorphism
Short Communication
type 2 diabetes mellitus
UGT1A9
oral clearance
type 2 diabetes mellitus
polymorphism
UGT1A9
dapagliflozin
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Summary: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.
Bibliography:Funding information
M. Daniel Naagaard and Roy Chang contributed equally.
The authors confirm that James List, MD, PhD was the Study Director of Study MB102008, the study in which the pharmacogenomic and pharmacokinetic samples were collected. Dr List was an employee of Bristol‐Myers Squibb (BMS) when he was involved in the study. The manuscript for this exploratory analysis objective of the study was written after Dr List left BMS and company policy is not to have ex‐employees as authors if they did not fully participate in the writing of the manuscript.
AstraZeneca
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Funding information AstraZeneca
ISSN:0306-5251
1365-2125
1365-2125
DOI:10.1111/bcp.15117