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.
Study Design
This was a phase I, open-label, two-period, fixed sequence study.
Setting
The study was performed at the Human Pharmacology Centre/Department of Translational Medicine, Boehringer Ingelheim, Biberach, Germany.
Participants
Eighteen healthy premenopausal women participated in the study.
Intervention
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).
Main Outcome Measures
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 (AUCτ,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 AUCτ,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.
Conclusion
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.
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Acknowledgments
The study was funded by Boehringer Ingelheim. The sponsor was responsible for the design and conduct of the study; the collection, management, analysis and interpretation of the data; the preparation, review and approval of the manuscript. All authors are employees of Boehringer Ingelheim. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Karen Pilgram and Wendy Morris, of Fleishman-Hillard Group Ltd., during the preparation of this manuscript. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version.
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Clinicaltrials.gov identifier: NCT01328184.
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Macha, S., Mattheus, M., Pinnetti, S. et al. Effect of Empagliflozin on the Steady-State Pharmacokinetics of Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers. Clin Drug Investig 33, 351–357 (2013). https://doi.org/10.1007/s40261-013-0068-y
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DOI: https://doi.org/10.1007/s40261-013-0068-y