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Pharmacokinetics of the first combination 17β-estradiol/progesterone capsule in clinical development for menopausal hormone therapy.

Pickar JH, Bon C, Amadio JM, Mirkin S, Bernick B - Menopause (2015)

Bottom Line: The extent of estradiol and progesterone absorption was similar between the test product and the reference products.The combination 17β-estradiol/progesterone product demonstrates bioavailability similar to those of the respective reference products of estradiol and progesterone.If regulatory approval is obtained, this new hormone therapy would be the first treatment of menopause symptoms to combine progesterone with 17β-estradiol in an oral formulation.

View Article: PubMed Central - PubMed

Affiliation: 1Columbia University Medical Center, New York, NY 2Biostudy Solutions LLC, Wilmington, NC 3TherapeuticsMD Inc, Boca Raton, FL.

ABSTRACT

Objective: This study aims to compare the pharmacokinetics and oral bioavailability of a capsule combining 17β-estradiol and progesterone in a non-peanut oil-containing formulation with those of widely used and approved separate formulations of estradiol and progesterone coadministered to healthy postmenopausal women.

Methods: This was an open-label, balanced, randomized, single-dose, two-treatment, three-period, three-sequence, cross-over, partial-replicate, reference-scaled study. Postmenopausal women (aged 40-65 y) were randomly assigned to one of three dosing sequences of test and reference products (TRR, RTR, or RRT, where T is the test drug and R is the coadministered reference product), with each of the three periods separated by a 14-day washout. The primary pharmacokinetic endpoints were Cmax, AUC(0-t), and AUC(0-inf) for the test and reference products, assessed for bioequivalence using the scaled average bioequivalence or unscaled average bioequivalence method. Safety was assessed by clinical observation, participant-reported adverse events, and laboratory data, including blood levels of hormones.

Results: Sixty-six women were randomly assigned, and 62 women (94.0%) completed all three study periods. All AUC and Cmax parameters met bioequivalence criteria for all analytes (estradiol, progesterone, and estrone), except Cmax for total estrone. The extent of estradiol and progesterone absorption was similar between the test product and the reference products. Four adverse events--all considered mild and unrelated to the study drugs--were reported.

Conclusions: The combination 17β-estradiol/progesterone product demonstrates bioavailability similar to those of the respective reference products of estradiol and progesterone. If regulatory approval is obtained, this new hormone therapy would be the first treatment of menopause symptoms to combine progesterone with 17β-estradiol in an oral formulation.

No MeSH data available.


Related in: MedlinePlus

Flow chart outlining the dosing procedure for each study period.
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Figure 1: Flow chart outlining the dosing procedure for each study period.

Mentions: We used SAS version 9.2 (SAS Institute Inc, Cary, NC) to generate a randomization schedule. Based on the randomized schedule, participants were assigned, in equal numbers, to one of three dosing sequences (TRR, RTR, or RRT, where T is the test drug and R is the coadministered reference product). In each sequence, participants received a single dose of TX-001HR in one study period and a single dose of estradiol plus a single dose of progesterone in each of the remaining two periods. The same doses of the test and reference products were used for all three study periods (Fig. 1). The dose in each of the three study periods was separated by a 14-day washout to eliminate drug carryover effects. Study randomization was balanced, and access to the randomization code was controlled.


Pharmacokinetics of the first combination 17β-estradiol/progesterone capsule in clinical development for menopausal hormone therapy.

Pickar JH, Bon C, Amadio JM, Mirkin S, Bernick B - Menopause (2015)

Flow chart outlining the dosing procedure for each study period.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4666011&req=5

Figure 1: Flow chart outlining the dosing procedure for each study period.
Mentions: We used SAS version 9.2 (SAS Institute Inc, Cary, NC) to generate a randomization schedule. Based on the randomized schedule, participants were assigned, in equal numbers, to one of three dosing sequences (TRR, RTR, or RRT, where T is the test drug and R is the coadministered reference product). In each sequence, participants received a single dose of TX-001HR in one study period and a single dose of estradiol plus a single dose of progesterone in each of the remaining two periods. The same doses of the test and reference products were used for all three study periods (Fig. 1). The dose in each of the three study periods was separated by a 14-day washout to eliminate drug carryover effects. Study randomization was balanced, and access to the randomization code was controlled.

Bottom Line: The extent of estradiol and progesterone absorption was similar between the test product and the reference products.The combination 17β-estradiol/progesterone product demonstrates bioavailability similar to those of the respective reference products of estradiol and progesterone.If regulatory approval is obtained, this new hormone therapy would be the first treatment of menopause symptoms to combine progesterone with 17β-estradiol in an oral formulation.

View Article: PubMed Central - PubMed

Affiliation: 1Columbia University Medical Center, New York, NY 2Biostudy Solutions LLC, Wilmington, NC 3TherapeuticsMD Inc, Boca Raton, FL.

ABSTRACT

Objective: This study aims to compare the pharmacokinetics and oral bioavailability of a capsule combining 17β-estradiol and progesterone in a non-peanut oil-containing formulation with those of widely used and approved separate formulations of estradiol and progesterone coadministered to healthy postmenopausal women.

Methods: This was an open-label, balanced, randomized, single-dose, two-treatment, three-period, three-sequence, cross-over, partial-replicate, reference-scaled study. Postmenopausal women (aged 40-65 y) were randomly assigned to one of three dosing sequences of test and reference products (TRR, RTR, or RRT, where T is the test drug and R is the coadministered reference product), with each of the three periods separated by a 14-day washout. The primary pharmacokinetic endpoints were Cmax, AUC(0-t), and AUC(0-inf) for the test and reference products, assessed for bioequivalence using the scaled average bioequivalence or unscaled average bioequivalence method. Safety was assessed by clinical observation, participant-reported adverse events, and laboratory data, including blood levels of hormones.

Results: Sixty-six women were randomly assigned, and 62 women (94.0%) completed all three study periods. All AUC and Cmax parameters met bioequivalence criteria for all analytes (estradiol, progesterone, and estrone), except Cmax for total estrone. The extent of estradiol and progesterone absorption was similar between the test product and the reference products. Four adverse events--all considered mild and unrelated to the study drugs--were reported.

Conclusions: The combination 17β-estradiol/progesterone product demonstrates bioavailability similar to those of the respective reference products of estradiol and progesterone. If regulatory approval is obtained, this new hormone therapy would be the first treatment of menopause symptoms to combine progesterone with 17β-estradiol in an oral formulation.

No MeSH data available.


Related in: MedlinePlus