Drug-drug Interaction of Empagliflozin (BI 10773) and Microgynon

An Open-label, Two-period, Fixed-sequence Trial to Evaluate the Effect of Multiple Doses of BI 10773 on the Multiple-dose Pharmacokinetics of a Combination of Ethinylestradiol and Levonorgestrel in Healthy Premenopausal Female Volunteers

The objective of this study is to investigate the possible effect of multiple oral doses of 25 mg BI 10773 on the steady state pharmacokinetics of ethinylestradiol (EE) and levonogestrel (LNG) (Microgynon®).

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: levonorgestrel; Drug: Ethinylestradiol; Drug: Microgynon + BI 10773

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Biberach, Germany
    • 1245.41.1 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 39 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion criteria:

1. Healthy female subjects

Exclusion criteria:

1. Any relevant deviation from healthy conditions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reference; multiple doses of Microgynon	Drug: levonorgestrel; multiple doses; Drug: Ethinylestradiol; multiple doses
Active Comparator: Test; multiple doses of Microgynon + BI 10773	Drug: levonorgestrel; multiple doses; Drug: Ethinylestradiol; multiple doses; Drug: Microgynon + BI 10773; multiple doses BI 10773

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ethinylestradiol: Area Under the Curve at Steady State Over the Uniform Dosing Interval τ (AUCτ,ss)	Area under the concentration-time curve of ethinylestradiol in plasma at steady state over the uniform dosing interval τ.	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Levonorgestrel: Area Under the Curve at Steady State Over the Uniform Dosing Interval τ (AUCτ,ss)	Area under the concentration-time curve of levonorgestrel in plasma at steady state over the uniform dosing interval τ.	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Ethinylestradiol: Maximum Measured Concentration (Cmax,ss)	Maximum measured concentration of ethinylestradiol in plasma at steady state over the uniform dosing interval τ.	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Levonorgestrel: Maximum Measured Concentration (Cmax,ss)	Maximum measured concentration of levonorgestrel in plasma at steady state over the uniform dosing interval τ.	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ethinylestradiol: Time From Last Dosing to Maximum Measured Concentration (Tmax,ss)	Time from last dosing to the maximum measured concentration of ethinylestradiol in plasma at steady state	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Levonorgestrel: Time From Last Dosing to Maximum Measured Concentration (Tmax,ss)	Time from last dosing to the maximum measured concentration of levonorgestrel in plasma at steady state	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Ethinylestradiol: Apparent Clearance at Steady State (CL/Fss)	Apparent clearance of ethinylestradiol in the plasma at steady state after oral administration	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Levonorgestrel: Apparent Clearance at Steady State (CL/Fss)	Apparent clearance of levonorgestrel in the plasma at steady state after oral administration	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Ethinylestradiol: Apparent Volume of Distribution During the Terminal Phase at Steady State (Vz/Fss)	Apparent volume of distribution during the terminal phase at steady state after oral administration	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Levonorgestrel: Apparent Volume of Distribution During the Terminal Phase at Steady State (Vz/Fss)	Apparent volume of distribution during the terminal phase at steady state after oral administration	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Ethinylestradiol: Terminal Half-life at Steady State (t1/2,ss)	Terminal half-life of ethinylestradiol in plasma at steady state	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Levonorgestrel: Terminal Half-life at Steady State (t1/2,ss)	Terminal half-life of levonorgestrel in plasma at steady state	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Ethinylestradiol: Terminal Rate Constant at Steady State (λz,ss)	Terminal rate constant of ethinylestradiol in plasma at steady state	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Levonorgestrel: Terminal Rate Constant at Steady State (λz,ss)	Terminal rate constant of levonorgestrel in plasma at steady state	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Ethinylestradiol: Mean Residence Time at Steady State (MRTpo,ss)	Mean residence time of ethinylestradiol in the body at steady state after oral administration	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Levonorgestrel: Mean Residence Time at Steady State (MRTpo,ss)	Mean residence time of levonorgestrel in the body at steady state after oral administration	Pre-dose, 30 min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration of Microgynon on Days 14 and 21. In addition, pre-dose samples were collected on Days 12, 13, 19, and 20.
Number of Participants With Clinically Relevant Abnormalities in Physical Examination, Vital Signs, ECG and Clinical Laboratory Tests.	Number of participants with clinically relevant abnormalities in physical examination, vital signs and clinical laboratory tests. Relevant findings or worsenings of baseline conditions were reported as adverse events.	Day 1 to day 17
Assessment of Tolerability	Tolerability will be assessed by the investigator according to the categories good, satisfactory, not satisfactory, bad and not assessable.	Within Day 24 to Day 31

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Macha S, Mattheus M, Pinnetti S, Woerle HJ, Broedl UC. 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. doi: 10.1007/s40261-013-0068-y.

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: April 1, 2011
• First Submitted That Met QC Criteria: April 1, 2011
• First Posted (Estimate): April 4, 2011

Study Record Updates

• Last Update Posted (Estimate): June 18, 2014
• Last Update Submitted That Met QC Criteria: May 16, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptive Agents, Female; Sodium-Glucose Transporter 2 Inhibitors; Contraceptives, Oral, Synthetic; Contraceptives, Oral, Hormonal; Contraceptives, Postcoital, Synthetic; Contraceptives, Postcoital; Contraceptives, Postcoital, Hormonal; Levonorgestrel; Ethinyl Estradiol; Empagliflozin; Ethinyl estradiol, levonorgestrel drug combination; Ethinyl Estradiol-Norgestrel Combination
• Other Study ID Numbers: 1245.41; 2010-023432-16 (EudraCT Number: EudraCT)