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

• Published in: Clinical therapeutics 2014-02, Vol.36 (2), p.280-290.e1
• Main Authors: Macha, Sreeraj, PhD, Koenen, Rüdiger, MD, Sennewald, Regina, MD, Schöne, Katja, Dipl-Math, Hummel, Noemi, DrSc, Riedmaier, Stephan, PhD, Woerle, Hans J., MD, Salsali, Afshin, MD, Broedl, Uli C., MD
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Benzhydryl Compounds - pharmacokinetics; Biological and medical sciences; Cross-Over Studies; Drug dosages; Drug Interactions; Drug therapy; Drug Therapy, Combination; empagliflozin; Female; Gemfibrozil - pharmacokinetics; Glucose; Glucosides - pharmacokinetics; Haplotypes; Humans; Internal Medicine; Male; Medical Education; Medical sciences; Metabolites; Middle Aged; organic anion transporters; Pharmacology. Drug treatments; Probenecid - pharmacokinetics; Rifampin - pharmacokinetics; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Studies; Substance abuse treatment; uridine diphosphate glucuronosyltransferase
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2014.01.003

Abstract 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/m2 . 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 (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