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Bioequivalence Evaluation of a Folate-Supplemented Oral Contraceptive Containing Ethinylestradiol/Drospirenone/Levomefolate Calcium versus Ethinylestradiol/Drospirenone and Levomefolate Calcium Alone

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Abstract

Background: Neural tube defects (NTDs) are congenital malformations that occur during early embryonic development. Suboptimal maternal folate status is a well-known risk factor for the occurrence of NTDs, and periconceptional folic acid supplementation has been shown to reduce the risk of NTDs. Folate-supplemented oral contraceptives (OCs) offer a means of improving folate status in women of childbearing potential by increasing their likelihood of having raised folate levels at the time of conception.

Objective: This study aimed to demonstrate bioequivalence of ethinylestradiol (EE), drospirenone and L-5-methyl-tetrahydrofolate (L-5-methyl-THF; active moiety of levomefolate calcium) when taken as a new folate-supplemented OC containing EE/drospirenone/levomefolate calcium, with the respective OC containing EE/drospirenone and a tablet containing levomefolate calcium only.

Methods: This was a randomized, open-label, three-period crossover study carried out at a single centre in Germany. The study included 45 healthy women (age range 18–38 years). The women were randomly assigned to single doses of (i) EE 0.03 mg/drospirenone 3 mg/levomefolate calcium 0.451 mg (SAFYRAL®), (ii) EE 0.03 mg/drospirenone 3 mg (Yasmin®), and (iii) levomefolate calcium 0.451 mg, administered using a crossover design, with one or more menstrual cycle washout between doses. The primary variables were maximum concentrations (Cmax) and area under the concentration versus time curve (AUC) values for EE, drospirenone and L-5-methyl-THF.

Results: The bioavailability of EE and drospirenone was similar after administration of EE/drospirenone/levomefolate calcium and EE/drospirenone. The geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) for AUC values and Cmax were within the pre-specified range (80.00–125.00%) for bioequivalence for EE and drospirenone in both formulations. The bioavailability of L-5-methyl-THF was similar after administration of EE/drospirenone/levomefolate calcium and levomefolate calcium. The respective GMRs and 90% CIs of baseline-uncorrected and -corrected AUClast (AUC from time zero to time of last measurable concentration) and Cmax were also within the 80.00–125.00% range.

Conclusion: The novel folate-supplemented OC EE/drospirenone/levomefolate calcium is bioequivalent to the established OC Yasmin® (EE/drospirenone components) and to levomefolate calcium (folate component).

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Acknowledgements

Levomefolate calcium was synthesized by Merck & Cie, Switzerland. The authors would like to thank Danielle Turner and Phil Jones of inScience Communications, Springer Healthcare, for medical writing assistance, which was funded by Bayer HealthCare Pharmaceuticals. The authors would also like to thank Reinhild Prinz-Langenohl, Susanne Reschke, Michaela Damaske, Marion Friedrich and Matthias Frei for support regarding the data collection, data management, analyses, graphs and tables.

Conflicts of Interests

Herbert Wiesinger, Dietmar Trummer, Hartmut Blode, Beate Rohde and Konstanze Diefenbach are employees of Bayer HealthCare Pharmaceuticals. Urte Eydeler is an employee of Scope International GmbH, the contract research organization that conducted the study, and has no other conflicts of interest to declare. Frank Richard was an employee of Bayer HealthCare Pharmaceuticals at the time that the study was conducted; Frank Richard has no other conflicts of interest to declare.

Role of Funding Source

Funding for the study design, study conduct, data collection and analysis was provided by Bayer HealthCare Pharmaceuticals, the manufacturer of the used drug products. All authors contributed to data collection and/or interpretation of data. All authors approved the decision to submit the manuscript.

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Authors and Affiliations

  1. Bayer HealthCare Pharmaceuticals, Müllerstrasse 170-178, D-13342, Berlin, Germany

    Herbert Wiesinger, Dietmar Trummer, Hartmut Blode, Beate Rohde & Konstanze Diefenbach

  2. Scope International GmbH, Hamburg, Germany

    Urte Eydeler

  3. Nycomed GmbH — A Takeda Company, Konstanz, Germany

    Frank Richard

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  1. Herbert Wiesinger
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  2. Urte Eydeler
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  4. Dietmar Trummer
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  7. Konstanze Diefenbach
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Correspondence to Herbert Wiesinger.

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Wiesinger, H., Eydeler, U., Richard, F. et al. Bioequivalence Evaluation of a Folate-Supplemented Oral Contraceptive Containing Ethinylestradiol/Drospirenone/Levomefolate Calcium versus Ethinylestradiol/Drospirenone and Levomefolate Calcium Alone. Clin Drug Investig 32, 673–684 (2012). https://doi.org/10.1007/BF03261921

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