Bioequivalence Study: 2 mg Estradiol Valerate (EV) and 3 mg Dienogest (DNG) Without and With Levomefolate Calcium

Study Overview
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Brief Summary
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Investigation of the bioequivalence (BE) of Estradiol Valerate (EV) and Dienogest (DNG) after administration of one film-coated tablet containing 2 mg Estradiol Valerate, 3 mg Dienogest and 0.451 mg Levomefolate calcium as compared to one film-coated tablet containing 2 mg Estradiol Valerate,3 mg Dienogest.Investigation of the bioequivalence of levomefolate calcium after administration of one film-coated tablet containing 2 mg Estradiol Valerate, 3 mg Dienogest and 0.451 mg Levomefolate calcium as compared to one film-coated tablet containing 0.451 mg levomefolate calcium

Official Title
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Open-label, Randomized, Cross-over Study to Investigate the Bioequivalence of Estradiol Valerate (EV), Dienogest (DNG) and Levomefolate Calcium After Single Oral Administration of a Tablet Formulation Containing 2 mg Estradiol Valerate and 3 mg Dienogest Without and With 0.451 mg Levomefolate Calcium and a Tablet Formulation Containing 0.451 mg Levomefolate Calcium in 42 Healthy Postmenopausal Women

Conditions
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Pharmacology, Clinical

Intervention / Treatment
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* Drug: BAY 98-7079, Estradiolvalerate (EV) / Dienogest (DNG) / Levomefolate calcium
* Drug: BAY 86-5027,Estradiolvalerate(EV) / Dienogest (DNG)
* Drug: BAY 86-7660,levomefolate calcium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy postmenopausal women, age: 45-75 years with body mass index between ≥18 and ≤30 kg/m2. Post-menopausal state revealed by: medical history, and hormone analyses in serum: estradiol ≤20 pg/mL and in women <60 years old: follicle-stimulating hormone ≥ 40 IU/L at screening Exclusion Criteria: Contraindications for use of combined (Estradiolvalerate/Dienogest) contraceptive (e.g.history of venous/arterial thromboembolic disease) Regular intake of medication Clinically relevant findings (ECG, blood pressure, physical and gynaecological examination, laboratory examination) Smoking

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Estradiol + dienogest + levomefolate<br>Treatment A | Drug: BAY 98-7079, Estradiolvalerate (EV) / Dienogest (DNG) / Levomefolate calcium<br>* Oral, single dose, 2 mg EV + 3 mg DNG + 0.451 mg levomefolate calcium washout phase between treatments: at least 7 days<br>|
| Active Comparator: Estradiol + dienogest<br>Treatment B | Drug: BAY 86-5027,Estradiolvalerate(EV) / Dienogest (DNG)<br>* Oral, single dose, 2 mg EV + 3 mg DNG washout phase between treatments: at least 7 days<br>|
| Active Comparator: Levomefolate<br>Treatment C | Drug: BAY 86-7660,levomefolate calcium<br>* Oral, single dose, 0.451 mg levomefolate calcium washout phase between treatments: at least 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC | Area under the concentration vs time curve from zero to infinity for DNG | Pre-dose and up to 72 hr post-dose for the treatments A and B and up to 12 hr post dose for the treatment C | 
| Cmax | Maximum drug concentration for DNG and for E1, E2, E1S, and L-5-methyl-THF (baseline corrected and uncorrected) | Pre-dose and up to 72 hr post-dose for the treatments A and B and up to 12 hr post dose for the treatment C | 
| AUC(0-tlast) | AUC from time 0 to the last data point above the lower limit of quantitation for E1, E2, E1S, and L-5-methyl-THF (baseline corrected and uncorrected) | Pre-dose and up to 72 hr post-dose for the treatments A and B and up to 12 hr post dose for the treatment C | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tmax | Time to reach maximum drug concentration in plasma for DNG and E1, E2, E1S, and L-5-methyl-THF (baseline uncorrected) | Pre-dose and up to 72 hr post-dose for the treatments A and B and up to 12 hr post dose for the treatment C | 
| t½ | Half-life associated with the terminal slope for DNG and E1, E2, E1S, and L-5-methyl-THF | Pre-dose and up to 72 hr post-dose for the treatments A and B and up to 12 hr post dose for the treatment C | 
| λz | Apparent terminal rate constant(estimates only) for DNG and E1, E2, E1S, and L-5-methyl-THF | Pre-dose and up to 72 hr post-dose for the treatments A and B and up to 12 hr post dose for the treatment C | 
| AUC(0-tlast) | AUC from time 0 to the last data point above the lower limit of quantitation for DNG | Pre-dose and up to 72 hr post-dose for the treatments A and B and up to 12 hr post dose for the treatment C | 
| AUC | Area under the concentration vs time curve from zero to infinity E1, E2, E1S, and L-5-methyl-THF (baseline corrected) | Pre-dose and up to 72 hr post-dose for the treatments A and B and up to 12 hr post dose for the treatment C |