Effects of rifampin and mefenamic acid on the pharmacokinetics and pharmacodynamics of dapagliflozin.
OBJECTIVE
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.


CONCLUSIONS
Modest changes in dapagliflozin exposure were seen with rifampin and mefenamic acid with minor changes in UGE, none of which were considered clinically meaningful.
Discovery Medicine & Clinical Pharmacology, Bristol-Myers Squibb, Princeton, NJ, USA. sreeneeranj.kasichayanula@bms.com
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Kasichayanula
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Liu
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Griffen
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Lacreta
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Boulton
D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005960:Glucosides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008528:Mefenamic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000090264:UDP-Glucuronosyltransferase 1A9
D001559:Benzhydryl Compounds; D004791:Enzyme Inhibitors; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C000715591:UGT1A9 protein, human; C529054:dapagliflozin; D008528:Mefenamic Acid; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D012293:Rifampin