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/m(2). Exposure to empagliflozin was increased by coadministration with gemfibrozil (AUC0-∞: geometric mean ratio [GMR], 158.50% [90% CI, 151.77-165.53]; Cmax: GMR, 115.00% [90% CI, 106.15-124.59]), rifampicin (AUC0-∞: GMR, 135.20% [90% CI, 129.58-141.06]; Cmax: GMR, 175.14% [90% CI, 160.14-191.56]), and probenecid (AUC0-∞: GMR, 153.47% [90% CI, 146.41-160.88]; Cmax: 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.
Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut. Electronic address: sreeraj.macha@boehringer-ingelheim.com.
Sreeraj
S
Macha
Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
Rüdiger
R
Koenen
Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
Regina
R
Sennewald
Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.
Katja
K
Schöne
Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
Noemi
N
Hummel
Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
Stephan
S
Riedmaier
Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.
Hans J
HJ
Woerle
Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.
Afshin
A
Salsali
Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.
Uli C
UC
Broedl
D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015248:Gemfibrozil / Q000493:pharmacokinetics*; D005960:Glucosides / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011339:Probenecid / Q000493:pharmacokinetics*; D012293:Rifampin / Q000493:pharmacokinetics*; D000077203:Sodium-Glucose Transporter 2 Inhibitors
D001559:Benzhydryl Compounds; D005960:Glucosides; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin; D011339:Probenecid; D015248:Gemfibrozil; D012293:Rifampin
drug interactions; empagliflozin; organic anion transporters; uridine diphosphate glucuronosyltransferase