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Effects of rifampin and mefenamic acid on the pharmacokinetics and pharmacodynamics of dapagliflozin
Author(s) -
Kasichayanula S.,
Liu X.,
Griffen S. C.,
LaCreta F. P.,
Boulton D. W.
Publication year - 2013
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12024
Subject(s) - dapagliflozin , mefenamic acid , pharmacokinetics , pharmacology , pharmacodynamics , chemistry , excretion , medicine , endocrinology , biochemistry , diabetes mellitus , type 2 diabetes
Aims Dapagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that decreases serum glucose by reducing renal glucose reabsorption, thereby promoting urinary glucose excretion. Dapagliflozin is primarily metabolized via the uridine diphosphate‐glucuronosyltransferase (UGT)1A9 pathway to its major inactive metabolite, dapagliflozin 3‐O‐glucuronide. The aim of this study was to evaluate the potential for drug‐drug interaction between dapagliflozin and two potential UGT1A9 modulators. Methods The results of two open‐label, non‐randomized, single‐sequence studies are reported in which the effects of rifampin (a pleiotropic drug‐metabolizing enzyme inducer; study 1) and mefenamic acid (a strong UGT1A9 inhibitor; study 2) were evaluated on the pharmacokinetics and pharmacodynamics (assessed by urinary glucose excretion [UGE]) of dapagliflozin in healthy subjects. In study 1, 14 subjects received single doses of dapagliflozin 10 mg alone and in the presence of rifampin 600 mg QD (6 days). In study 2, 16 subjects received single doses of dapagliflozin 10 mg alone and in the presence of mefenamic acid 250 mg q6h (5 days). Results Rifampin reduced total exposure (area under the concentration‐time curve from time 0 to infinity [AUC0‐inf]) to dapagliflozin by 22% and mefenamic acid increased dapagliflozin AUC0‐inf by 51%. No clinically meaningful effect of rifampin or mefenamic acid on the pharmacokinetics of dapagliflozin or on dapagliflozin‐mediated urinary glucose excretion was observed. Conclusion Modest changes in dapagliflozin exposure were seen with rifampin and mefenamic acid with minor changes in UGE, none of which were considered clinically meaningful.