EE-drospirenone-levomefolate calcium versus EE-drospirenone + folic acid: folate status during 24 weeks of treatment and over 20 weeks following treatment cessation

Konstanze Diefenbach, Dietmar Trummer, Frank Ebert, Michael Lissy, Manuela Koch, Beate Rohde, Hartmut Blode, Konstanze Diefenbach, Dietmar Trummer, Frank Ebert, Michael Lissy, Manuela Koch, Beate Rohde, Hartmut Blode

Abstract

Background: Adequate folate supplementation in the periconceptional phase is recommended to reduce the risk of neural tube defects. Oral contraceptives may provide a reasonable delivery vehicle for folate supplementation before conception in women of childbearing potential. This study aimed to demonstrate that a fixed-dose combination of an oral contraceptive and levomefolate calcium leads to sustainable improvements in folate status compared with an oral contraceptive + folic acid.

Methods: This was a double-blind, randomized, parallel-group study in which 172 healthy women aged 18-40 years received ethinylestradiol (EE)-drospirenone-levomefolate calcium or EE-drospirenone + folic acid for 24 weeks (invasion phase), and EE-drospirenone for an additional 20 weeks (folate elimination phase). The main objective of the invasion phase was to examine the area under the folate concentration time-curve for plasma and red blood cell (RBC) folate, while the main objective of the elimination phase was to determine the duration of time for which RBC folate concentration remained ≥ 906 nmol/L after cessation of EE-drospirenone-levomefolate calcium.

Results: Mean concentration-time curves for plasma folate, RBC folate, and homocysteine were comparable between treatment groups during both study phases. During the invasion phase, plasma and RBC folate concentrations increased and approached steady-state after about 8 weeks (plasma) or 24 weeks (RBC). After cessation of treatment with levomefolate calcium, folate concentrations decreased slowly. The median time to RBC folate concentrations falling below 906 nmol/L was 10 weeks (95% confidence interval 8-12 weeks) after cessation of EE-drospirenone-levomefolate calcium treatment. Plasma and RBC folate levels remained above baseline values in 41.3% and 89.3% of women, respectively, at the end of the 20-week elimination phase.

Conclusion: Improvements in folate status were comparable between EE-drospirenone-levomefolate calcium and EE-drospirenone + folic acid. Plasma and RBC folate levels remained elevated for several months following cessation of treatment with EE-drospirenone-levomefolate calcium.

Keywords: drospirenone; ethinylestradiol; folic acid; levomefolate calcium; neural tube defect; oral contraception.

Figures

Figure 1
Figure 1
Treatment schedule. Notes: Cycles were repeated five times (ie, six treatment cycles) during the 24-week invasion phase and four times (ie, five treatment cycles) during the 20-week elimination phase. All treatments were administered once daily. aEE 0.030 mg–drospirenone 3 mg–levomefolate calcium 0.451 mg tablet; blevomefolate calcium 0.451 mg tablet AND placebo capsule; cEE 0.030 mg–drospirenone 3 mg; dfolic acid 0.400 mg capsule; eplacebo tablet AND folic acid 0.400 mg capsule; fno tablets or capsules. Abbreviations: drsp, drospirenone; EE, ethinylestradiol; HFI, hormone-free interval.
Figure 2
Figure 2
Disposition of women throughout the study. Abbreviations: drsp, drospirenone; EE, ethinylestradiol.
Figure 3
Figure 3
Concentration-time curves for plasma folate during 24 weeks of treatment with EE-drospirenone-levomefolate calcium or EE-drospirenone + folic acid (invasion phase) and during the 20-week period following cessation of treatment (elimination phase; per protocol set). Notes: Vertical lines indicate the mean ± standard deviation. Values prior to week 0 represent the three pretreatment measurements that were used to calculate the mean median baseline value. Vertical dotted line indicates the cutoff between the two phases. Abbreviations: drsp, drospirenone; EE, ethinylestradiol.
Figure 4
Figure 4
Concentration-time curves for RBC folate during 24 weeks of treatment with EE-drospirenone-levomefolate calcium or EE-drospirenone + folic acid (invasion phase) and during the 20-week period following cessation of treatment (elimination phase; per protocol set). Notes: Vertical lines indicate the mean ± standard deviation. Values prior to week 0 represent the three pre-treatment measurements that were used to calculate the mean median baseline value. Vertical dotted line indicates the cutoff between the two phases. Abbreviations: drsp, drospirenone; EE, ethinylestradiol; RBC, red blood cell.
Figure 5
Figure 5
Kaplan–Meier estimates for time to RBC folate levels falling below 906 nmol/L for EE-drospirenone following treatment with EE-drospirenone-levomefolate calcium (per protocol set). Abbreviations: EE, ethinylestradiol; RBC, red blood cell.
Figure 6
Figure 6
Distribution of individual L-MTHF plasma concentrations [nmol/L] at baseline (visit 1), week 12 (visit 8), and week 24 (visit 14) after daily oral administration of EE-drospirenone-levomefolate calcium (MTHF) or EE-drospirenone + FA. Note: Lower level of quantification for L-MTHF was between 3.325 and 3.680 nmol/L. Abbreviations: EE, ethinylestradiol; FA, folic acid; L-MTHF, L-5-methyl-tetrahydrofolate.
Figure 7
Figure 7
Percentages of metabolite values below lower limit of quantification at baseline (visit 1), week 12 (visit 8), and week 24 (visit 14) after daily oral administration of EE-drospirenone-levomefolate calcium (MTHF) and EE-drospirenone + FA. Abbreviations: EE, ethinylestradiol; FA, folic acid; MTHF, 5-methyl-tetrahydrofolate.

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