Pharmacokinetic studies of solubilized estradiol given vaginally in a novel softgel capsule

Figures & data

Table 1. Demographic characteristics of the subjects who completed the studies.

	10-μg Study (n = 35)		25-μg Study (n = 36)
	Parameter	Mean ± SD	Range	Mean ± SD	Range
Age (years)		50.40 ± 4.96	42.00–63.00	49.86 ± 3.83	43.00–58.00
Height (cm)	150.14 ± 5.13	140.00–161.00	149.69 ± 5.42	135.00–162.00
Weight (kg)	57.26 ± 8.59	43.00–73.00	57.47 ± 6.83	50.00–75.00
Body mass index (kg/m^2)	25.36 ± 3.32	18.73–29.90	25.61 ± 2.24	21.64–29.90

SD, standard deviation

Table 2. Mean estrogen values in pharmacokinetic trials (geometric mean; baseline adjusted), and ANOVA results for comparisons between test^a and reference^b products. p Values indicate statistical significance at <0.05 between test and reference products.

	AUC0-24 (pg·h/ml)			Cmax (pg/ml)			tmax (h)
	Dose (μg)	Test	Reference	p	Test	Reference	p	Test	Reference
Estradiol
10	49.62	132.92	<0.0001	14.38	20.38	0.0194	1.75	9.28
25	89.21	292.1	<0.0001	23.08	42.70	<0.0001	1.85	11.18
Estrone
10	24.24	48.24	0.0002	5.15	6.98	0.0127	5.87	9.07
25	50.22	165.5	<0.0001	10.69	23.58	0.0002	5.14	11.48
Estrone sulfate
10	66.6 (ng·h/dl)	121.6 (ng·h/dl)	0.0091	12.2 (ng/dl)	16.9 (ng/dl)	0.0366	5.5	8.8
25	4290	7330	0.0031	497.6	730.6	0.0042	11.75	15.87

^a, Test product: TX-004HR; TherapeuticsMD, Inc., Boca Raton, FL, USA; ^b, reference product: Vagifem®; Novo Nordisk, Plainsboro, NJ, USA.

Figure 1. Linear plot of baseline-corrected mean plasma concentration versus time for (a) estradiol (n = 34), (b) estrone (n = 33), and (c) estrone sulfate (n = 24) after treatment with the test and reference preparations, each at 10 μg. Test product: TX-004HR; TherapeuticsMD, Inc., Boca Raton, FL. Reference product: Vagifem®; Novo Nordisk, Plainsboro, NJ.

Figure 2. Linear plot of baseline-corrected mean plasma concentration versus time for (a) estradiol (n = 36), (b) estrone (n = 36), and (c) estrone sulfate (n = 36) after treatment with the test and reference preparations, each at 25 μg. Test product: TX-004HR; TherapeuticsMD, Inc., Boca Raton, FL. Reference product: Vagifem®; Novo Nordisk, Plainsboro, NJ.

Table 3. Statistical results of test product versus reference product for estrogens (baseline-adjusted).

	10-μg dose^a			25-μg dose^b
	Analyte/parameter	Intra-subject CV%	Test-to-reference ratio^c (×100)	90% CI	Intra-subject CV%	Test-to-reference ratio^c (×100)	90% CI
Estradiol
AUC0-24 (pg·h/ml)	70.64	37.95	29.21–49.31	70.4	30.5	23.7–39.3
Cmax (pg/ml)	60.68	71.54	56.82–90.08	54.0	54.1	44.2–66.1
Estrone
AUC0-24 (pg·h/ml)	73.66	50.51	38.37–66.50	157	31.0	19.8–48.4
Cmax (pg/ml)	47.59	74.50	61.69–89.97	99.6	45.8	33.0–63.6
Estrone sulfate
AUC0–24 (10 μg: ng.h/dl; 25 μg: pg.h/ml)	73.87	57.87	41.68–80.35	82.6	57.8	43.2–77.3
Cmax (10 μg: ng/dl; 25 μg: pg/ml)	48.02	74.55	59.43–93.51	58.8	67.1	53.8–83.6

CV, coefficient of variation; CI, confidence interval

^a, estradiol, n = 34; estrone, n = 33; estrone sulfate, n = 24; ^b, estradiol, n = 36; estrone and estrone sulfate, n = 35; ^c, test product: TX-004HR; TherapeuticsMD, Inc., Boca Raton, FL, USA; reference product: Vagifem®; Novo Nordisk, Plainsboro, NJ, USA. All test–reference ratios are statistically significant by ANOVA (α = 0.05)