title: Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers.
abstract: BACKGROUND
  Empagliflozin is a potent, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of patients with type 2 diabetes mellitus. Oral contraceptives may be co-administered with antidiabetic agents over long periods of time, therefore potential drug-drug interactions between oral contraceptives and antidiabetic drugs should be investigated.
  
  
  OBJECTIVE
  The effect of multiple oral doses of empagliflozin 25 mg once daily (qd) on the steady-state pharmacokinetics of the combined oral contraceptive ethinylestradiol (EE) 30 μg/levonorgestrel (LNG) 150 μg qd was investigated.
  
  
  METHODS
  This was a phase I, open-label, two-period, fixed sequence study.
  
  
  METHODS
  The study was performed at the Human Pharmacology Centre/Department of Translational Medicine, Boehringer Ingelheim, Biberach, Germany.
  
  
  METHODS
  Eighteen healthy premenopausal women participated in the study.
  
  
  METHODS
  There was a mandatory run-in period in which participants received EE 30 μg/LNG 150 μg qd for 21-48 days followed by a treatment-free interval of 7 days. Participants then received EE 30 μg/LNG 150 μg qd for 14 days (reference; period 1), followed by EE 30 μg/LNG 150 μg qd plus empagliflozin 25 mg qd for 7 days (test; period 2).
  
  
  METHODS
  The pharmacokinetics of EE and LNG at steady state based on the primary endpoints of area under the steady-state plasma concentration-time curve during a dosage interval τ (AUC(τ,ss)) and maximum steady-state plasma concentration during a dosage interval (C (max,ss)) were the main outcome measures.
  
  
  RESULTS
  The pharmacokinetics of EE and LNG were not affected by co-administration with empagliflozin. Geometric mean ratios (90 % CI) of AUC(τ,ss) and C (max,ss) for EE were 102.82 % (97.58, 108.35) and 99.22 % (93.40, 105.39), respectively. For LNG, these values were 101.94 % (98.54, 105.47) and 105.81 % (99.47, 112.55), respectively. The 90 % CIs were within the standard bioequivalence boundaries of 80-125 %. There were no relevant changes in the time to reach peak levels (t (max,ss)) or terminal elimination half-life (t (½,ss)) of EE and LNG between test and reference treatments. Ten women in each treatment had at least one adverse event (AE). Severe AEs were reported by three women in the reference period and one woman in the test period. There were no serious AEs or premature discontinuations.
  
  
  CONCLUSIONS
  The combination of EE 30 μg/LNG 150 μg and empagliflozin 25 mg was well tolerated. Based on standard bioequivalence criteria, empagliflozin had no effect on the pharmacokinetics of EE and LNG, indicating that no dose adjustment of EE 30 μg/LNG 150 μg is required when empagliflozin is co-administered.
authors.affiliation: Clinical Pharmacokinetics and Pharmacodynamics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. sreeraj.macha@boehringer-ingelheim.com
authors.forename: Sreeraj
authors.initials: S
authors.lastname: Macha
authors.forename: Michaela
authors.initials: M
authors.lastname: Mattheus
authors.forename: Sabine
authors.initials: S
authors.lastname: Pinnetti
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Woerle
authors.forename: Uli C
authors.initials: UC
authors.lastname: Broedl
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003278:Contraceptives, Oral, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005858:Germany; D005960:Glucosides / Q000008:administration & dosage* / Q000009:adverse effects; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016912:Levonorgestrel / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D019338:Polypharmacy; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D003277:Contraceptives, Oral, Combined; D003278:Contraceptives, Oral, Hormonal; D005960:Glucosides; D007004:Hypoglycemic Agents; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; C570240:empagliflozin