Effect of Gemfibrozil, Rifampicin, or Probenecid on the Pharmacokinetics of the SGLT2 Inhibitor Empagliflozin in Healthy Volunteers

Background: Empagliflozin is a potent, oral, selective: inhibitor of sodium glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. Objective: The goal of these studies was to investigate potential drug drug interactions between empagliflozin and gemfibrozil (an organic anion-transporting polypeptide 1B1 [OATP1B1]/1B3 and organic anion transporter 3 [OAT3] inhibitor), rifampicin (an OATP1B1/1B3 inhibitor), or probenecid (an OAT3 and uridine diphosphate glucuronosyltransferase inhibitor). Methods: Two open-label, randomized, crossover studies were undertaken in healthy subjects. In the first study, 18 subjects received the following in 1 of 2 randomized treatment sequences: a single dose of empagliflozin 25 mg alone and gemfibrozil 600 mg BID for 5 days with a single dose of empagliflozin 25 mg On the third day. In the second study, 18 subjects received a single dose of empagliflozin 10 mg, a single dose of empagliflozin 10 mg coadministered with a single dose of rifampicin 600 mg, and probenecid 500 mg BID for 4 days with a single dose of empagliflozin 10 mg on the second day in 1 of 6 randomized treatment sequences. Results: In the gemfibrozil study, 11 subjects were male, mean age was 35.1 years and mean body mass index (BMI) was 23.47 kg/m(2). In the rifampicin/probenecid study, 10 subjects were male, mean age was 32.7 years and mean BMI was 23.03 kg/m2. Exposure to empagliflozin was increased by coadministration with gemfibrozil (AUC(0-infinity): geometric mean ratio [GMR], 158.50% [90% CI, 151.77-165.53]; C-max: GMR, 115.00% [90% CI, 106.15-124.59]), rifampicin (AUCO3: GMR, 135.20% [90% CI, 129.58-141.06]; C-max: GMR, 175.14% [90% CI, 160.14-191.56]), and probenecid (AUC(0-infinity): GMR, 153.47% [90% CI, 146.41-160.88]; C-max: GMR, 125.60% [90% CI, 113.67-138.78]). All treatments were well tolerated. Conclusions: Increases in empagliflozin exposure were <2-fold, indicating that the inhibition of the OATP1B1/1B3, OAT3 transporter, and uridine diphosphate glucuronosyltransferases did not have a clinically relevant effect on empagliflozin exposure. No dose adjustments of empagliflozin were necessary when it was coadministered with gemfibrozil, rifampicin, or probenecid. ClinicalTrials.gov identifiers: NCT01301742 and NCT01634100. (Clin Ther. 2014;36:280-290) (C) 2014 Elsevier HS Journals, Inc. All rights reserved.