title: A vaginal estradiol softgel capsule, TX-004HR, has negligible to very low systemic absorption of estradiol: Efficacy and pharmacokinetic data review.
abstract: This paper reviews the efficacy, safety, and systemic absorption of estradiol with TX-004HR, an investigational, low-dose 17β-estradiol vaginal softgel capsule, designed to treat vulvar and vaginal atrophy (VVA) in postmenopausal women, with an improved user experience. In phase 2 (NCT02449902) and phase 3 REJOICE (NCT02253173) studies, TX-004HR significantly improved the proportions of vaginal superficial and parabasal cells and vaginal pH, and in the phase 3 study decreased the severity of dyspareunia, vaginal dryness, and vulvar and/or vaginal itching or irritation. In two randomized, phase 1 trials, estradiol Cmaxand AUC0-24were significantly lower with 10μg and 25μg TX-004HR than with the same doses of an approved vaginal estradiol tablet. A substudy (n=72) of the REJOICE trial showed that estradiol Cavgand AUC0-24with 4μg and 10μg TX-004HR were not different from placebo on days 1 and 14. While TX-004HR 25μg was associated with higher Cavgand AUC0-24versus placebo on days 1 and 14, these levels remained within the postmenopausal range. Estradiol day-84 values for all three doses were not different from placebo, demonstrating no estradiol accumulation. All TX-004HR doses were well tolerated and had an acceptable safety profile in all reviewed studies. The local vaginal efficacy of TX-004HR was significantly better than that of placebo, while the overall safety profile was similar to that of placebo. Negligible to very low systemic estradiol absorption was observed whether given at 4, 10, or 25μg. If approved, TX-004HR may be an alternative option for women with symptomatic VVA without increasing mean systemic estradiol absorption above postmenopausal levels.
authors.affiliation: The George Washington University School of Medicine, Washington, DC, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Simon
authors.affiliation: Clinical Research Center, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA, United States.
authors.forename: David F
authors.initials: DF
authors.lastname: Archer
authors.affiliation: EndoRheum Consultants, LLC, Malvern, PA, United States.
authors.forename: Ginger D
authors.initials: GD
authors.lastname: Constantine
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: James H
authors.initials: JH
authors.lastname: Pickar
authors.affiliation: TherapeuticsMD, Boca Raton, FL, United States.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Amadio
authors.affiliation: TherapeuticsMD, Boca Raton, FL, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Bernick
authors.affiliation: TherapeuticsMD, Boca Raton, FL, United States.
authors.forename: Shelli
authors.initials: S
authors.lastname: Graham
authors.affiliation: TherapeuticsMD, Boca Raton, FL, United States. Electronic address: smirkin@therapeuticsmd.com.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mirkin
mesh_terms: D065567:Absorption, Physiological; D000282:Administration, Intravaginal; D001284:Atrophy; D002214:Capsules; D004311:Double-Blind Method; D004414:Dyspareunia / Q000188:drug therapy; D004958:Estradiol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy / Q000379:methods; D004967:Estrogens / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D017698:Postmenopause; D014621:Vagina / Q000473:pathology; D014623:Vaginal Diseases / Q000188:drug therapy*; D014844:Vulva / Q000473:pathology; D014845:Vulvar Diseases / Q000188:drug therapy*
chemical_list: D002214:Capsules; D004967:Estrogens; D004958:Estradiol
keywords: Dyspareunia; Efficacy; Estradiol; Menopause; Pharmacokinetics; TX-004HR; Vaginal atrophy