TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol

Objective: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. Methods:A substudy of the REJOICE trial (multicenter, double-blind, placebo-controlled, phase 3) evaluated the pharmacokinetics of 4, 10, and 25-mu g 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, t(max), C-min, C-avg, and C-max for estradiol, estrone, and estrone conjugates. Results:Seventy-two women (mean 59 y) participated. TX-004HR 4 mu g showed no statistical differences from placebo in estradiol pharmacokinetic (PK) parameters. At 10 mu g, estradiol C-max was statistically higher than placebo on day 1, but was not different from placebo on day 14. With 25-mu g, estradiol PK parameters were statistically higher than placebo. Estradiol C-avg values for 25 mu g were 9.1pg/mL on day 1 and 7.1pg/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. Conclusions: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 mu g, and only minor increases were observed with 25 mu g (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.