title: TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol.
abstract: To evaluate the pharmacokinetics of TX-004HR vaginal estradiol softgel capsules when used for treating moderate-to-severe dyspareunia in postmenopausal women with vulvar and vaginal atrophy.
  
  
  
  A substudy of the REJOICE trial (multicenter, double-blind, placebo-controlled, phase 3) evaluated the pharmacokinetics of 4, 10, and 25-μg TX-004HR doses once/d for 2 weeks, followed by twice/wk for 10 weeks. Serum samples obtained at 2, 4, 6, 10, and 24 hours postdose on days 1 and 14, and once on day 84, were analyzed for area under the serum concentration-time curve, tmax, Cmin, Cavg, and Cmax for estradiol, estrone, and estrone conjugates.
  
  
  
  Seventy-two women (mean 59 y) participated. TX-004HR 4 μg showed no statistical differences from placebo in estradiol pharmacokinetic (PK) parameters. At 10 μg, estradiol Cmax was statistically higher than placebo on day 1, but was not different from placebo on day 14. With 25 μg, estradiol PK parameters were statistically higher than placebo. Estradiol Cavg values for 25 μg were 9.1 pg/mL on day 1 and 7.1 pg/mL on day 14. Estrone and estrone conjugate PK parameters with TX-004HR were lower than or similar to placebo across all doses. No drug accumulation was observed.
  
  
  
  Vaginal TX-004HR resulted in negligible to very low systemic absorption of estradiol. No statistical differences in estradiol PK parameters were observed on day 14 with 4 and 10 μg, and only minor increases were observed with 25 μg (within the normal postmenopausal range). This PK substudy, in conjunction with the primary efficacy results, demonstrated that TX-004HR provided local benefits of estradiol with limited systemic exposure.
authors.affiliation: 1Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 2EndoRheum Consultants, LLC, Malvern, PA 3The George Washington University School of Medicine, Washington, DC 4BioMedical Computer Research Institute, Inc, Philadelphia, PA 5Independent Consultant, West Chester, PA 6TherapeuticsMD, Boca Raton, FL.
authors.forename: David F
authors.initials: DF
authors.lastname: Archer
authors.forename: Ginger D
authors.initials: GD
authors.lastname: Constantine
authors.forename: James A
authors.initials: JA
authors.lastname: Simon
authors.forename: Harvey
authors.initials: H
authors.lastname: Kushner
authors.forename: Philip
authors.initials: P
authors.lastname: Mayer
authors.forename: Brian
authors.initials: B
authors.lastname: Bernick
authors.forename: Shelli
authors.initials: S
authors.lastname: Graham
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mirkin
mesh_terms: D065567:Absorption, Physiological; D000282:Administration, Intravaginal; D000328:Adult; D000368:Aged; D001284:Atrophy; D002170:Canada; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004414:Dyspareunia / Q000097:blood / Q000188:drug therapy*; D004958:Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause; D016896:Treatment Outcome; D014481:United States; D014621:Vagina / Q000473:pathology*
chemical_list: C000626288:TX-004HR; D004958:Estradiol