Investigation of Bioequivalence of Ethinylestradiol (EE) and Drospirenone (DRSP) in Two Different Tablet Formulations: YAZ and YAZ + Levomefolate Calcium (Metafolin) & L-5-MTHF in Two Different Tablet Formulations: Levomefolate Calcium (Metafolin) and YAZ + Levomefolate Calcium (Metafolin)

Phase 1

Completed

Conditions: Contraception

Interventions: Drug: EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300)
Drug: EE 0.02 mg/DRSP 3 mg/L-5-MTHF Ca 0.451 mg (EE20/DRSP/L-5-MTHF Ca)
Drug: L-5-MTHF 0.451mg (Metafolin)

Registration Number: NCT01253187

Lead Sponsor: Bayer

Brief Summary: The purpose of this study is examine and compare the uptake of YAZ (oral contraceptive containing drospirenone and ethinylestradiol) with or without levomefolate calcium (Metafolin, a registered vitamin supplement) in the body and to examine and compare the uptake of levomefolate calcium with or without YAZ in the body, in healthy volunteers not using hormonal contraception

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 44

Inclusion Criteria

Healthy female volunteer
Age: 18 - 38 years inclusive
Body mass index (BMI)1: ≥ 19 and < 28 kg/m²
Regular cyclic menstrual periods at screening OR when using combined oral contraceptives during the recruitment period reporting of natural cyclic menstrual periods prior to their use
Willingness to use non-hormonal methods of contraception during the complete trial OR previous tubal ligation

Exclusion Criteria

incompletely cured pre-existing diseases for which it can be assumed that the absorption, distribution, metabolism, excretion and effect of the study drugs will not be normal
known or suspected sex-steroid influenced malignancies
endometrial hyperplasia; genital bleeding of unknown origin; uterus myomatosus
known or suspected tumors of the liver and pituitary
presence or history of severe hepatic disease as long as liver function values have not returned to normal
severe renal insufficiency or acute renal failure
thrombophlebitis, venous / arterial thromboembolic diseases; presence or history of prodromi of a thrombosis
other conditions that increase susceptibility to thromboembolic diseases
known neuropsychiatric diseases, especially known or suspected epilepsy, and/ or deficient status of folate or vitamin B12
use of any other medication within 2 cycles before first study drug administration which could affect the study aim
use of potassium sparing drugs; use of folic acid containing supplements or medicines or use of any medication within 2 cycles before first study drug administration known to interfere with folate metabolism
inadequate folate and/or Vitamin B12 status, clinically relevant deviations in red cell folate concentrations

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300)	EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300)	single oral administration of 1 film-coated SHT00186D tablet (YAZ), containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP)
EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca)	EE 0.02 mg/DRSP 3 mg/L-5-MTHF Ca 0.451 mg (EE20/DRSP/L-5-MTHF Ca)	single oral administration of 1 film-coated SHT04532B tablet, containing 0.020 mg ethinylestradiol (EE) + 3 mg drospirenone (DRSP) + 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium \[MTHF-Ca\])
L-5-MTHF Ca 0.451 mg (Metafolin)	L-5-MTHF 0.451mg (Metafolin)	single oral administration of 1 coated SHT04532C tablet, containing 0.451 mg Metafolin (L-5-methyltetrahydrofolate calcium \[MTHF-Ca\])

Primary Outcome Measures

Name	Time	Method
Mean Maximum Concentration (Cmax) of EE Incl. Bioequivalence (BE) Evaluation	up to 96 hours after administration	Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample
Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of EE Incl. Bioequivalence (BE) Evaluation	up to 96 hours after administration	The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample
Mean Maximum Concentration (Cmax) of DRSP Incl. Bioequivalence (BE) Evaluation	up to 168 hours after administration	Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample
Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of DRSP Incl. Bioequivalence (BE) Evaluation	up to 168 hours after administration	The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample
Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Corrected) Incl. Bioequivalence (BE) Evaluation	up to 12 hours after administration	The baseline corrected Cmax is a measure of the highest measured drug concentration provided solely by the treatment after subtracting endogenous L-5-methyl-THF level. It is obtained by collecting a series of blood samples, measuring the concentrations of L-5-methyl-THF in each sample and by subtracting the pre-treatment concentration.
Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of L-5-methyl-THF (Baseline Corrected) Incl. Bioequivalence (BE) Evaluation	up to 12 hours after administration	The baseline corrected AUC is a measure of the systemic drug exposure provided by the treatment excluding the endogenous L-5-methyl-THF level. It is obtained by collecting a series of blood samples, measuring the concentrations of L-5-methyl-THF in each sample and by subtracting the pre-treatment concentration.
Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Uncorrected) Incl. Bioequivalence (BE) Evaluation	up to 12 hours after administration	The baseline uncorrected Cmax is a measure of the highest measured drug concentration including the endogenous L-5-methyl-THF level. It is obtained by collecting a series of blood samples and measuring the concentrations of L-5-methyl-THF in each sample.
Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of L-5-methyl-THF (Baseline Uncorrected) Incl. Bioequivalence (BE) Evaluation	up to 12 hours after administration	The baseline uncorrected AUC is a measure of the systemic drug exposure provided by the treatment including the endogenous L-5-methyl-THF level. It is obtained by collecting a series of blood samples and measuring the concentrations of L-5-methyl-THF in each sample.

Secondary Outcome Measures

Name	Time	Method
Time to Reach Maximum Concentration (Tmax) of EE	up to 96 hours after administration	Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content
Mean Area Under the Concentration-time Curve From Administration up to 72h AUC(0-72h) of DRSP	up to 72 hours after administration	The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample
Time to Reach Maximum Concentration (Tmax) of DRSP	up to 168 hours after administration	Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content
Time to Reach Maximum Concentration (Tmax) of L-5-methyl-THF	up to 12 hours after administration	Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content