Bioequivalence evaluation of a folate-supplemented oral contraceptive containing ethinylestradiol/drospirenone/levomefolate calcium versus ethinylestradiol/drospirenone and levomefolate calcium alone.
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 (C(max)) 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 C(max) 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 AUC(last) (AUC from time zero to time of last measurable concentration) and C(max) were also within the 80.00-125.00% range.


CONCLUSIONS
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).
Bayer HealthCare Pharmaceuticals, Berlin, Germany. herbert.wiesinger@bayer.com
Herbert
H
Wiesinger
Urte
U
Eydeler
Frank
F
Richard
Dietmar
D
Trummer
Hartmut
H
Blode
Beate
B
Rohde
Konstanze
K
Diefenbach
D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000736:Androstenes / Q000493:pharmacokinetics; D019540:Area Under Curve; D002118:Calcium / Q000493:pharmacokinetics; D003278:Contraceptives, Oral, Hormonal / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004997:Ethinyl Estradiol / Q000493:pharmacokinetics; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000378:metabolism; D005971:Glutamates / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D000451:Mineralocorticoid Receptor Antagonists / Q000493:pharmacokinetics*; D009752:Nutritional Status; D013763:Tetrahydrofolates / Q000097:blood; D014815:Vitamins / Q000008:administration & dosage / Q000378:metabolism; D055815:Young Adult
D000736:Androstenes; D003278:Contraceptives, Oral, Hormonal; D005971:Glutamates; D000451:Mineralocorticoid Receptor Antagonists; D013763:Tetrahydrofolates; D014815:Vitamins; D004997:Ethinyl Estradiol; D005492:Folic Acid; C569381:levomefolate calcium; C035144:drospirenone; D002118:Calcium; C005984:5-methyltetrahydrofolate