Contraception
Conditions
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
Interventions
DRUGEE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300)
Treatment group A: Single 1 film-coated tablet (Ethinylestradiol \[EE\] 0.02mg / Drospirenone \[DRSP\] 3mg) taken orally under fasting condition at intervals of at least one menstrual cycle.
DRUGEE 0.02 mg/DRSP 3 mg/L-5-MTHF Ca 0.451 mg (EE20/DRSP/L-5-MTHF Ca)
Treatment group B: Single 1 film-coated tablet (Ethinylestradiol \[EE\] 0.02mg / Drospirenone \[DRSP\] 3mg / L-5-methyltetrahydrofolate \[L-5-MTHF\] 0.451mg) taken orally under fasting condition at intervals of at least one menstrual cycle.
DRUGL-5-MTHF 0.451mg (Metafolin)
Treatment group C: Single 1 coated tablet (L-5-methyltetrahydrofolate \[L-5-MTHF\] 0.451mg) taken orally under fasting condition at intervals of at least one menstrual cycle.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 38 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
Countries
Netherlands
Participant flow
Recruitment details
Healthy young women, aged 18 - 38 years inclusive, who were nonsmokers were enrolled from 20 October 2006 to 13 September 2007 at one center in Germany.
Pre-assignment details
77 female volunteers were screened according to the inclusion and exclusion criteria to determine that the volunteer was in a good state of health and appropriate for inclusion in the study, and 44 volunteers were randomized at one center.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes all participants treated | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
| Period 3 | difficulty with blood sampling | 0 | 1 | 0 | 0 | 0 | 0 |
| Period 3 | non-compliance | 0 | 0 | 0 | 0 | 1 | 0 |
| Period 3 | Pregnancy | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age Continuous | 26.3 Years STANDARD_DEVIATION 6.33 |
| Sex: Female, Male Female | 44 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 37 / 43 | 30 / 41 | 34 / 43 |
| serious Total, serious adverse events | 0 / 43 | 0 / 41 | 0 / 43 |
Outcome results
Primary
Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of DRSP Incl. Bioequivalence (BE) Evaluation
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 frame: up to 168 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of DRSP Incl. Bioequivalence (BE) Evaluation | 386 ng·h/mL |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of DRSP Incl. Bioequivalence (BE) Evaluation | 383 ng·h/mL |
Comparison: 33 volunteers qualified for statistical analysis of BE whereas all 35 (YAZ) and 36 (EE20/DRSP/L-5-MTHF Ca) volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis90% CI: [97.28, 103.79]ANOVA
Primary
Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of EE Incl. Bioequivalence (BE) Evaluation
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 frame: up to 96 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of EE Incl. Bioequivalence (BE) Evaluation | 358 pg·h/mL |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | Mean Area Under the Concentration-time Curve From Administration to the Last Measurement [AUC(0-tlast)] of EE Incl. Bioequivalence (BE) Evaluation | 370 pg·h/mL |
Comparison: 38 volunteers qualified for statistical analysis of BE whereas all 39 volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis90% CI: [99.16, 107.98]ANOVA
Primary
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
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.
Time frame: up to 12 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | 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 | 214 nmol·h/L |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | 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 | 217 nmol·h/L |
Comparison: 39 volunteers qualified for statistical analysis of BE whereas all 39 (EE20/DRSP/L-5-MTHF Ca) and 40 (Metafolin) volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis90% CI: [93.95, 102.57]ANOVA
Primary
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
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.
Time frame: up to 12 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | 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 | 370 nmol·h/L |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | 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 | 370 nmol·h/L |
Comparison: 40 volunteers qualified for statistical analysis of BE and all 40 volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis90% CI: [95.38, 104.58]ANOVA
Primary
Mean Maximum Concentration (Cmax) of DRSP Incl. Bioequivalence (BE) Evaluation
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
Time frame: up to 168 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | Mean Maximum Concentration (Cmax) of DRSP Incl. Bioequivalence (BE) Evaluation | 25.4 ng/mL |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | Mean Maximum Concentration (Cmax) of DRSP Incl. Bioequivalence (BE) Evaluation | 26.7 ng/mL |
Comparison: 33 volunteers qualified for statistical analysis of BE whereas all 35 (YAZ) and 36 (EE20/DRSP/L-5-MTHF Ca) volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis90% CI: [97.3, 113.83]ANOVA
Primary
Mean Maximum Concentration (Cmax) of EE Incl. Bioequivalence (BE) Evaluation
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
Time frame: up to 96 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | Mean Maximum Concentration (Cmax) of EE Incl. Bioequivalence (BE) Evaluation | 39.6 pg/mL |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | Mean Maximum Concentration (Cmax) of EE Incl. Bioequivalence (BE) Evaluation | 41.9 pg/mL |
Comparison: 38 volunteers qualified for statistical analysis of BE whereas all 39 volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis90% CI: [98.86, 113.72]ANOVA
Primary
Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Corrected) Incl. Bioequivalence (BE) Evaluation
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.
Time frame: up to 12 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Corrected) Incl. Bioequivalence (BE) Evaluation | 44.3 nmol/L |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Corrected) Incl. Bioequivalence (BE) Evaluation | 44.2 nmol/L |
Comparison: 39 volunteers qualified for statistical analysis of BE whereas all 39 (EE20/DRSP/L-5-MTHF Ca) and 40 (Metafolin) volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis90% CI: [91.24, 109.34]ANOVA
Primary
Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Uncorrected) Incl. Bioequivalence (BE) Evaluation
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.
Time frame: up to 12 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Uncorrected) Incl. Bioequivalence (BE) Evaluation | 57.9 nmol/L |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | Mean Maximum Concentration (Cmax) of L-5-methyl-THF (Baseline Uncorrected) Incl. Bioequivalence (BE) Evaluation | 57.7 nmol/L |
Comparison: 40 volunteers qualified for statistical analysis of BE and all 40 volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis90% CI: [93.15, 107.95]ANOVA
Secondary
Mean Area Under the Concentration-time Curve From Administration up to 72h AUC(0-72h) of DRSP
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 frame: up to 72 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | Mean Area Under the Concentration-time Curve From Administration up to 72h AUC(0-72h) of DRSP | 350 ng·h/mL |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | Mean Area Under the Concentration-time Curve From Administration up to 72h AUC(0-72h) of DRSP | 344 ng·h/mL |
Comparison: 32 volunteers qualified for statistical analysis of BE whereas all 34 (YAZ) and 36 (EE20/DRSP/L-5-MTHF Ca) volunteers with valid concentration time profiles were included in the pharmacokinetic (PK) analysis90% CI: [97.65, 103.02]ANOVA
Secondary
Time to Reach Maximum Concentration (Tmax) of DRSP
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 frame: up to 168 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | Time to Reach Maximum Concentration (Tmax) of DRSP | 2.00 hours |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | Time to Reach Maximum Concentration (Tmax) of DRSP | 2.00 hours |
Secondary
Time to Reach Maximum Concentration (Tmax) of EE
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 frame: up to 96 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | Time to Reach Maximum Concentration (Tmax) of EE | 1.50 hours |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | Time to Reach Maximum Concentration (Tmax) of EE | 1.52 hours |
Secondary
Time to Reach Maximum Concentration (Tmax) of L-5-methyl-THF
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 frame: up to 12 hours after administration
Population: Note that not all samples were evaluable for each outcome measure. Therefore the number of participants analyzed not necessarily matches the number of completers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EE 0.02 mg/DRSP 3 mg (YAZ, BAY86-5300) | Time to Reach Maximum Concentration (Tmax) of L-5-methyl-THF | 0.50 hours |
| EE 0.02mg/DRSP 3mg/L-5-MTHF Ca 0.451mg (EE20/DRSP/L-5-MTHF Ca) | Time to Reach Maximum Concentration (Tmax) of L-5-methyl-THF | 0.50 hours |