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

Figures & data

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 Disposition of women throughout the study.

Abbreviations: drsp, drospirenone; EE, ethinylestradiol.

Table 1 Baseline and demographic characteristics of study participants (per protocol set)

	EE-drsp-levomefolate calcium (n = 75)	EE-drsp + folic acid (n = 75)
Age, years	28.2 ± 5.7	27.0 ± 5.5
Height, cm	165.9 ± 6.3	167.1 ± 5.5
Body weight, kg	63.3 ± 8.2	62.8 ± 8.6
Body mass index, kg/m^2	23.0 ± 2.6	22.5 ± 2.6
Current smoker, n (%)	22 (29.3)	21 (28.0)

Note: Data are presented as the mean ± standard deviation unless otherwise stated.

Abbreviations: drsp, drospirenone; EE, ethinylestradiol.

Table 2 Area under the folate concentration-time curve from time 0 (baseline) to week 24 (AUC_{(0–24 weeks)}) for plasma and RBC folate (uncorrected and corrected for baseline folate concentrations) after administration of EE-drospirenone-levomefolate calcium or EE-drospirenone + folic acid for 24 weeks (invasion phase; per protocol set)

	Plasma folate AUC(0–24 weeks) (nmol week/L)		RBC folate AUC(0–24 weeks) (nmol week/L)
	Baseline-uncorrected	Baseline-corrected	Baseline-uncorrected	Baseline-corrected
EE-drsp-levomefolate calcium (n = 75)	1030 (24.0)	640 (29.0)	24,176 (21.8)	10,427 (34.3)
EE-drsp + folic acid (n = 75)	904 (22.3)	561 (32.7)	21,876 (17.7)	8863 (24.6)

Note: Data presented as geometric mean (% geometric coefficient of variation).

Abbreviation: AUC, area under the concentration-time curve; drsp, drospirenone; EE, ethinylestradiol; RBC, red blood cell.

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 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.

Table 3 Proportion of women (cumulative) with plasma and RBC folate levels below the mean median baseline value, and with homocysteine levels above the mean median baseline value in the 20-week period following the cessation of 24 weeks of treatment with EE-drospirenone-levomefolate calcium or EE-drospirenone + folic acid (per protocol set)

Week	Plasma folate		RBC folate		Homocysteine
	Levomefolate calcium	Folic acid	Levomefolate calcium	Folic acid	Levomefolate calcium	Folic acid
26	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	4 (5.3)	2 (2.7)
28	4 (5.3)	4 (5.3)	0 (0.0)	0 (0.0)	8 (10.7)	5 (6.7)
30	5 (6.7)	8 (10.7)	0 (0.0)	0 (0.0)	11 (14.7)	9 (12.0)
32	11 (14.7)	12 (16.0)	0 (0.0)	0 (0.0)	14 (18.7)	12 (16.0)
34	15 (20.0)	17 (22.7)	1 (1.3)	0 (0.0)	16 (21.3)	14 (18.7)
36	23 (30.7)	23 (30.7)	2 (2.7)	2 (2.7)	19 (25.3)	17 (22.7)
38	25 (33.3)	25 (33.3)	2 (2.7)	2 (2.7)	20 (26.7)	23 (30.7)
40	30 (40.0)	34 (45.3)	6 (8.0)	2 (2.7)	22 (29.3)	26 (34.7)
42	30 (40.0)	38 (50.7)	7 (9.3)	3 (4.0)	25 (33.3)	29 (38.7)
44	44 (58.7)	45 (60.0)	8 (10.7)	6 (8.0)	26 (34.7)	30 (40.0)

Notes: Data are n (%). The mean median baseline values were as follows for EE-drospirenone-levomefolate calcium and EE-drospirenone + folic acid, respectively: plasma folate, 16.4 and 14.1 nmol/L; RBC folate, 578.3 and 550.2 nmol/L; homocysteine, 9.3 and 9.2 μmol/L.

Abbreviations: EE, ethinylestradiol; RBC, red blood cells.

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 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 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.

Table 4 Mean metabolite concentrations in plasma (nmol/L)

	EE-drsp-levomefolate calcium		EE-drsp + folic acid
	THF	5,10-methenyl-THF	THF	5,10-methenyl-THF
Baseline	4.07 ± 0.357 (n = 4)	1.57 ± 0.412 (n = 9)	4.60 ± 0.656 (n = 7)	1.63 ± 0.372 (n = 8)
Week 12	4.98 ± 1.851 (n = 13)	1.76 ± 0.603 (n = 7)	5.28 ± 1.806 (n = 14)	1.45 ± 0.282 (n = 7)
Week 24	5.92 ± 2.318 (n = 23)	1.46 ± 0.238 (n = 12)	5.76 ± 2.835 (n = 19)	1.95 ± 1.166 (n = 12)

Notes: Values are presented as the mean ± standard deviation. Lower level of quantification = THF, between 3.447 and 3.539 nmol/L; 5,10-methenyl-THF, between 1.052 and 1.284 nmol/L.

Abbreviations: drsp, drospirenone; EE, ethinylestradiol; THF, tetrahydrofolate.

Table 5 Adverse events during the invasion phase, elimination phase, and the overall study (invasion + elimination phase)

	Treatment during invasion phase
	EE-drsp-levomefolate calcium	EE-drsp + folic acid
Invasion phase
AEs, %	96.5	95.3
TEAEs, %	30.2	15.1
SAEs, n	2 in 1 woman	2 in 2 women
Elimination phase
AEs, %	87.5	91.5
TEAEs, %	8.8	11.0
SAEs, n	9 in 5 women	3 in 1 woman

Abbreviations: AE, adverse event; drsp, drospirenone; EE, ethinylestradiol; SAE, serious AE; TEAE, treatment-emergent AE.