title: Effect of multiple oral doses of linagliptin on the steady-state pharmacokinetics of a combination oral contraceptive in healthy female adults: an open-label, two-period, fixed-sequence, multiple-dose study.
abstract: BACKGROUND
  Linagliptin is an oral dipeptidyl peptidase (DPP)-4 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. Microgynon® 30 is a combined oral contraceptive pill containing both ethinylestradiol 30 μg and levonorgestrel 150 μg (EE 30 μg/LNG 150 μg).
  
  
  OBJECTIVE
  The objective of this study was to determine the effect of multiple doses of linagliptin (5 mg once daily) on the steady-state pharmacokinetics of EE and LNG following once-daily doses of EE 30 μg/LNG 150 μg.
  
  
  METHODS
  This was an open-label, two-period, fixed-sequence, multiple-dose study, consisting of a run-in period, a 14-day reference treatment period and a 7-day test treatment period. The study recruited 18 healthy pre-menopausal female subjects aged 18-40 years with a body mass index of 18.5-27.0 kg/m2. Only women with regular menstrual cycles were included in this study. The treatment sequence was divided into three steps: an individually tailored run-in period with EE 30 μg/LNG 150 μg to synchronize the menstrual cycles of the subjects followed by a washout period of 7 days; the reference treatment period, during which EE 30 μg/LNG 150 μg alone was taken on days 1-14; and the test treatment period, during which EE 30 μg/LNG 150 μg plus linagliptin were taken on days 15-21. The pharmacokinetic parameters measured were maximum steady-state plasma concentration during a dosage interval (C(max,ss)), time to reach maximum plasma concentration following administration at steady state (t(max,ss)) and area under the plasma concentration-time curve during a dosage interval (τ) at steady state (AUC(τ,ss)).
  
  
  RESULTS
  The AUC(τ,ss) and C(max,ss) of EE and LNG were comparable when EE 30 μg/LNG 150 μg was given alone or combined with linagliptin. The adjusted geometric mean ratios for AUC(τ,ss) and C(max,ss) of EE following EE 30 μg/LNG 150 μg plus linagliptin versus EE 30 μg/LNG 150 μg alone were 101.4 (90% CI 97.2, 105.8) and 107.8 (90% CI 99.7, 116.6), respectively. The adjusted geometric mean ratios for AUC(τ,ss) and C(max,ss) of LNG following EE 30 μg/LNG 150 μg plus linagliptin versus EE 30 μg/LNG 150 μg alone were 108.8 (90% CI 104.5, 113.3) and 113.5 (90% CI 106.1, 121.3), respectively. The combination was well tolerated.
  
  
  CONCLUSIONS
  Linagliptin had no clinically relevant effect on the steady-state pharmacokinetics of EE and LNG in healthy female subjects, and the combination of EE 30 μg/LNG 150 μg and linagliptin was well tolerated in this study. Therefore, linagliptin has the potential to be used in the treatment of female patients with type 2 diabetes in combination with oral contraceptives containing these components, such as EE 30 μg/LNG 150 μg.
  
  
  BACKGROUND
  The EudraCT number for this study is 2008-000953-37.
authors.affiliation: Boehringer Ingelheim Pharma GmbH Co. KG, Biberach, Germany. Christian.Friedrich@boehringer-ingelheim.com
authors.forename: Christian
authors.initials: C
authors.lastname: Friedrich
authors.forename: Andreas
authors.initials: A
authors.lastname: Port
authors.forename: Arne
authors.initials: A
authors.lastname: Ring
authors.forename: Ulrike
authors.initials: U
authors.lastname: Graefe-Mody
authors.forename: Thomas
authors.initials: T
authors.lastname: Giessmann
authors.forename: Mario
authors.initials: M
authors.lastname: Iovino
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Woerle
mesh_terms: D000328:Adult; D019540:Area Under Curve; D003277:Contraceptives, Oral, Combined / Q000009:adverse effects / Q000493:pharmacokinetics; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D016912:Levonorgestrel / Q000009:adverse effects / Q000493:pharmacokinetics*; D000069476:Linagliptin; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D003277:Contraceptives, Oral, Combined; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004338:Drug Combinations; D011687:Purines; D011799:Quinazolines; C072593:ethinyl estradiol, levonorgestrel drug combination; D000069476:Linagliptin; D004997:Ethinyl Estradiol; D016912:Levonorgestrel