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Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers.
Clin Drug Investig. 2013 May; 33(5):351-7.CD

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 (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.

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.

Authors+Show Affiliations

Clinical Pharmacokinetics and Pharmacodynamics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. sreeraj.macha@boehringer-ingelheim.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23512637

Citation

Macha, Sreeraj, et al. "Effect of Empagliflozin On the Steady-state Pharmacokinetics of Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers." Clinical Drug Investigation, vol. 33, no. 5, 2013, pp. 351-7.
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. 2013;33(5):351-7.
Macha, S., Mattheus, M., Pinnetti, S., Woerle, H. J., & Broedl, U. C. (2013). Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers. Clinical Drug Investigation, 33(5), 351-7. https://doi.org/10.1007/s40261-013-0068-y
Macha S, et al. Effect of Empagliflozin On the Steady-state Pharmacokinetics of Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers. Clin Drug Investig. 2013;33(5):351-7. PubMed PMID: 23512637.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers. AU - Macha,Sreeraj, AU - Mattheus,Michaela, AU - Pinnetti,Sabine, AU - Woerle,Hans J, AU - Broedl,Uli C, PY - 2013/3/21/entrez PY - 2013/3/21/pubmed PY - 2013/10/29/medline SP - 351 EP - 7 JF - Clinical drug investigation JO - Clin Drug Investig VL - 33 IS - 5 N2 - 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 (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. 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. SN - 1179-1918 UR - https://www.unboundmedicine.com/medline/citation/23512637/Effect_of_empagliflozin_on_the_steady_state_pharmacokinetics_of_ethinylestradiol_and_levonorgestrel_in_healthy_female_volunteers_ L2 - https://dx.doi.org/10.1007/s40261-013-0068-y DB - PRIME DP - Unbound Medicine ER -