A Randomized, Open-Label, Crossover Study to Evaluate the Pharmacokinetics of Empagliflozin and Linagliptin After Coadministration in Healthy Male Volunteers

摘要

Background: Empagliflozin is an oral, potent, and selective inhibitor of sodium glucose cotransporter 2, inhibition of which reduces renal glucose reabsorption and results in increased urinary glucose excretion. Linagliptin is an oral inhibitor of dipeptidyl pepti- dase-4 approved for the treatment of type 2 diabetes in the United States, Europe, Japan, and Canada. Due to their complementary modes of action, there is a good rationale to combine empagliflozin with linagliptin to improve glycemic control in patients with type 2 diabetes. Objective: This study was conducted to investigate the pharmacokinetics of empagliflozin and linagliptin after coadministration in healthy volunteers. Methods: Thiswas an open-label, randomized,mul-tiple-dose, crossover study with 3 treatments in 2 treat-ment sequences. Sixteen healthy male subjects received treatment A (empagliflozin 50 mg once daily [QD] for 5 days), treatment B (empagliflozin 50 mg QD and linagliptin 5mgQD for 7 days), and treatment C (linagliptin 5 mg QD for 7 days) in sequence AB then C, or sequence C then AB. Results: Sixteen healthy male subjects aged between 18 and 50 years with a bodymass index of 18.5 to 29.9 kg/m2 were included in the study. Linagliptin total ex-posure (AUC over a uniform dosing interval Τ at steady state geometric mean ratio [GMR], 1.03 [90%CI, 0.96-1.11]) and peak exposure (Cmax at steady state GMR, 1.01 [90% CI, 0.87-1.19) exposure was unaffected by coadministration of empagliflozin. empagliflozin total exposure (AUC over a uniformdosing interval Τ at steady state GMR, 1.02 [90% CI, 0.97-1.07]) was unaffected by coadministration of linagliptin. There was a reduction in empagliflozin peak exposure (Cmax at steady state GMR, 0.88 [90% CI, 0.79-0.99]) when linagliptin was coadministered that was not considered clinically mean-ngful. No adverse events were reported during the coad-ministration period. No hypoglycemiawas reported. Em-paglifozin and linagliptin were well tolerated. Conclusion: These data support the coadministration of empagliflozin and linagliptin without dose adjust-ments. European Union Drug Regulating Authorities Clinical Trials Registration: EudraCT 2008-006089-27.