title: Pharmacokinetics of the first combination 17β-estradiol/progesterone capsule in clinical development for menopausal hormone therapy.
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.
authors.affiliation: 1Columbia University Medical Center, New York, NY 2Biostudy Solutions LLC, Wilmington, NC 3TherapeuticsMD Inc, Boca Raton, FL.
authors.forename: James H
authors.initials: JH
authors.lastname: Pickar
authors.forename: Charles
authors.initials: C
authors.lastname: Bon
authors.forename: Julia M
authors.initials: JM
authors.lastname: Amadio
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mirkin
authors.forename: Brian
authors.initials: B
authors.lastname: Bernick
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001682:Biological Availability; D004338:Drug Combinations; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004970:Estrone / Q000097:blood; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D008593:Menopause / Q000502:physiology*; D008875:Middle Aged; D011374:Progesterone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency
chemical_list: D004338:Drug Combinations; D004970:Estrone; D011374:Progesterone; D004958:Estradiol