title: A randomized, open-label, crossover study to evaluate the pharmacokinetics of empagliflozin and linagliptin after coadministration in healthy male volunteers.
abstract: 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 peptidase-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
  This was an open-label, randomized, multiple-dose, crossover study with 3 treatments in 2 treatment 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 5 mg QD 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 body mass index of 18.5 to 29.9 kg/m(2) were included in the study. Linagliptin total exposure (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 (C(max) 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 uniform dosing 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 (C(max) at steady state GMR, 0.88 [90% CI, 0.79-0.99]) when linagliptin was coadministered that was not considered clinically meaningful. No adverse events were reported during the coadministration period. No hypoglycemia was reported. Empagliflozin and linagliptin were well tolerated.
  
  
  CONCLUSIONS
  These data support the coadministration of empagliflozin and linagliptin without dose adjustments. European Union Drug Regulating Authorities Clinical Trials Registration: EudraCT 2008-006089-27.
authors: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. christian.friedrich@boehringer-ingelheim.com
authors: Christian
authors: C
authors: Friedrich
authors: Katrin
authors: K
authors: Metzmann
authors: Peter
authors: P
authors: Rose
authors: Michaela
authors: M
authors: Mattheus
authors: Sabine
authors: S
authors: Pinnetti
authors: Hans J
authors: HJ
authors: Woerle
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005858:Germany; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D000069476:Linagliptin; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005960:Glucosides; D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000069476:Linagliptin; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; C570240:empagliflozin; D005947:Glucose