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

Background: Linagliptin is an oral dipeptidyl peptidase (DPP)-4 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. Microgynon (R) 30 is a combined oral contraceptive pill containing both ethinylestradiol 30 mu g and levonorgestrel 150 mu g (EE 30 mu g/LNG 150 mu g). 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 mu g/LNG 150 mu g. 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/m(2). 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 mu g/LNG 150 mu g to synchronize the menstrual cycles of the subjects followed by a washout period of 7 days; the reference treatment period, during which EE 30 mu g/LNG 150 mu g alone was taken on days 1-14; and the test treatment period, during which EE 30 mu g/LNG 150 mu g plus linagliptin were taken on days 15-21. The pharmacolcinetic parameters measured were maximum steady-state plasma concentration during a dosage interval (C-max,C-ss), time to reach maximum plasma concentration following administration at steady state (t(max,ss)), 1 and area under the plasma, concentration-time curve during a dosage interval (tau) at steady state (AUC(tau,ss)). Results: The AUC(tau,ss), and C-max,C-ss of EE and LNG were comparable when EE 30 mu g/LNG 150 mu g was given alone or combined with linagliptin. The adjusted geometric mean ratios for AUC(tau,ss) and C-max,C-ss of EE following EE 30 mu g/LNG 150 mu g plus linagliptin versus EE 30 mu g/LNG 150 mu g 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(tau,ss) and C-max,C-ss of LNG following EE 30 mu g/LNG 150 mu g plus linagliptin versus EE 30 mu g/LNG 150 mu g 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. Conclusion: 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 mu g/LNG 150 mu g 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 mu g/LNG 150 mu g.