Bioavailability of Dienogest and Ethinyl Estradiol Tablets 2.0 mg/0.03 mg With Regards to Reference Product

Study Overview
=================
Brief Summary
-----------------
This Pilot study will investigate the bioavailability in fasting women of 2 tablet formulations containing Dienogest 2.0 mg and Ethinyl estradiol 0.03 mg. The Pilot study will be performed at a single site with 10 subjects. Participants will take 2 tablets of the test product and reference product in 2 periods and 2 sequences (either test after reference or reference after test). There will be a washout of at least 14 days between each study period.

Detailed Description
-----------------
The primary objective of the study is to investigate the relative bioavailability of Dienogest and Ethinyl estradiol of 2 tablet formulations with Dienogest 2.0 mg and Ethinyl estradiol 0.03 mg and to demonstrate bioequivalence of both formulations in terms of rate and extent of absorption: Test Product: Product manufactured by Laboratorios Andrómaco S.A. Reference Product: Valette [Trademark], product of Jenapharm, Germany. The 90% confidence intervals for the intra-subject coefficient of variation (Test versus Reference Product) for the main pharmacokinetic parameters area under the plasma concentration-time curve from time zero to time t (AUC0-t) and from time zero to 72 hours (AUC0-72), and maximum plasma concentration (Cmax) for total Dienogest and Ethinyl estradiol will be determined. Participants will be confined in the study site for approximately 36 hours during each study period (for 12 hours pre-dosing and for 24 hours post dosing) during which pharmacokinetic (PK) blood samples will be obtained. 16 blood samples will be taken up to 24 hours after the administration in each period. Participants will return to the site to provide additional blood samples at 48 h, and 72 h post-dose. The washout period between the two study periods will be at least 14 days. The samples from each participant will be analyzed with 2 methods of high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays to quantify total Dienogest and Ethinyl estradiol in plasma. The safety objective is to evaluate the tolerability of both formulations in women by collecting adverse events.

Official Title
-----------------
Bioavailability of a Formulation of Dienogest and Ethinyl Estradiol 2.0 mg/0.03 mg Coated Tablets With Regards to the Marketed Reference Product

Conditions
-----------------
Bioequivalence

Intervention / Treatment
-----------------
* Drug: Dienogest 2.0 mg and Ethinyl estradiol 0.03 mg Test Drug
* Drug: Dienogest 2.0 mg and Ethinyl estradiol 0.03 mg Reference Product


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Non-pregnant and non-breastfeeding women Women of childbearing age with an acceptable form of contraception during the study 18 to 55 years old inclusive; BMI greater than or equal to 18.51 and less than or equal to 29.99 Non-smoking or smoke only 3 cigarettes every 7 days With results of laboratory tests, electrocardiogram and chest radiography in normal and / or negative or abnormal ranges but without clinical relevance and declared suitable for study by the doctor after the physical examination Capable to understand the Informed Consent Form Exclusion Criteria: Study site staff or family members With history of drug and/or alcohol abuse Smokers more tan 3 cigarettes every 7 days Vitamin supplements intake 7 days prior to the administration of the medications under study Any recent change in eating habits or physical exercise Using of a pharmacological therapy (except over the counter medication use 7 days prior to the study) Hypersensitivity to the study drug or to other chemically related compounds, history of serious adverse reactions or hypersensitivity to any medication Use, during the 28 days prior to the start of the study, of medications known to alter liver enzyme activity Consumption of beverages or food containing grapefruit or pink grapefruit, within 7 days prior to each administration of the study medication and consumption of alcohol, caffeine or beverages or foods containing xanthines 24 hours before each administration of the study medication until the last sample of each period History of any significant cardiovascular disease Acute disease that generates significant physiological changes from the time of selection until the end of the study HIV, Hepatitis B and/or C positive Presence or history of thrombophlebitis, thrombosis or thromboembolic disorders, deep vein thrombosis, pulmonary embolism or known coagulopathy. Donation or loss of a significant volume (more than 100 mL) of blood or plasma or platelets during the 3 months prior to the start of the study Subjects who have participated in any type of clinical study during the 3 months prior to the start of the study History of any gastrointestinal surgery that could affect drug absorption Presence of fainting history or fear to blood collection

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dienogest and Ethinyl estradiol Test Product<br>Participants will receive two tablets of the test formulation containing Dienogest 2.0 mg and Ethinyl estradiol 0.03 mg. The tablets will be taken with water and in a fasting condition. | Drug: Dienogest 2.0 mg and Ethinyl estradiol 0.03 mg Test Drug<br>* Coated Tablets<br>* Other names: Investigational Medicinal Product;|
| Active Comparator: Dienogest and Ethinyl estradiol Reference Product<br>Participants will receive two tablets of the marketed reference formulation containing Dienogest 2.0 mg and Ethinyl estradiol 0.03 mg. The tablets will be taken with water and in a fasting condition. | Drug: Dienogest 2.0 mg and Ethinyl estradiol 0.03 mg Reference Product<br>* Coated Tablets<br>* Other names: Valette (Trademark);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Ethinyl estradiol: area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72) ] | 21 samples up to 72 hours will be taken after the administration in each period. | From tablet intake and up to 72 hours after tablet intake | 
| Total Dienogest: area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72) | 21 samples up to 72 hours will be taken after the administration in each period. | From tablet intake and up to 72 hours after tablet intake | 
| Total Ethinyl estradiol: area under the plasma concentration-time curve from 0 to time t (AUC0-t) | 21 samples up to 72 hours will be taken after the administration in each period. | From tablet intake and up to 72 hours after tablet intake | 
| Total Dienogest: area under the plasma concentration-time curve from 0 to time t (AUC0-t) | 21 samples up to 72 hours will be taken after the administration in each period. | From tablet intake and up to 72 hours after tablet intake | 
| Total Ethinyl estradiol: Maximum plasma concentration (Cmax) | 21 samples up to 72 hours will be taken after the administration in each period. | From tablet intake and up to 72 hours after tablet intake | 
| Total dienogest: Maximum plasma concentration (Cmax) | 21 samples up to 72 hours will be taken after the administration in each period. | From tablet intake and up to 72 hours after tablet intake | 
| Total dienogest: Time to achieve maximum plasma concentration (tmax) | 21 samples up to 72 hours will be taken after the administration in each period. | From tablet intake and up to 72 hours after tablet intake | 
| Total Ethinyl estradiol: Time to achieve maximum plasma concentration (tmax) | 21 samples up to 72 hours will be taken after the administration in each period. | From tablet intake and up to 72 hours after tablet intake |