Systemic Estradiol Absorption Low With Vaginal Capsule

Miriam E. Tucker

October 22, 2014

NATIONAL HARBOR, Maryland — An investigational solubilized estradiol capsule (VagiCap, TherapeuticsMD) could offer an option for treating vulvovaginal atrophy with even less systemic absorption than the currently available tablet (Vagifem, Novo Nordisk), early data suggest.

James H. Pickar, MD, adjunct professor of obstetrics and gynecology at Columbia University College of Physicians and Surgeons, New York City, presented the findings from phase 2 and pharmacokinetic studies here at the North American Menopause Society (NAMS) 2014 Annual Meeting.

"I think people are always concerned about systemic absorption.... Admittedly, the amount of absorption with Vagifem is pretty small, but this is even less. And that's the plus," Dr Pickar told Medscape Medical News.

Session moderator Katherine M. Newton, PhD, director of research and external affairs and senior investigator at Group Health Research Institute, Seattle, Washington, told Medscape Medical News, "Vagifem has been found to be safe. But for women who want as low exposure as possible to estrogen, this could be of interest."

Dr Pickar presented the results from two randomized, two-way, crossover, open-label bioavailability studies of 10-µg and 25-µg capsule (VagiCap) doses, comparing them to the tablet (Vagifem), as well as a phase 2 single-center, randomized, placebo-controlled clinical study testing the safety and efficacy of the half-inch capsule for 14 days.

The 71 women in the two bioavailability studies were generally healthy, between the ages of 40 and 65 years, with no vaginal bleeding for at least 12 months or 6 months post bilateral oophorectomy. In each study, 36 women received a single vaginal dose of the capsule or the tablet (both inserted by a nurse). Blood estrogen levels were measured at 13 time points from 1 hour prior to insertion to 24 hours after.

After adjustment for baseline levels, area under the curve values were 63% (10 µg) and 69% (25 µg) lower for estradiol with the capsule vs the tablet, and 50% (10 µg) and 70% (25 µg) lower for estrone. Peak estradiol concentrations were 29% less with the 10-µg dose and 46% less with 25-µg dose; peak estrone concentrations were 26% and 55% less, respectively.

Systemic exposure was significantly lower with both doses of the capsule than with equivalent doses of the tablet. There were no adverse events in either trial, Dr Pickar reported.

The phase 2 clinical study investigated use of the 10-µg estradiol capsule once daily for 14 days in 50 healthy postmenopausal women aged 40 to 75 years who inserted the capsule themselves. All had moderate to severe symptoms of vulvovaginal atrophy, with superficial cells 5% or less and a vaginal pH greater than 5.0.

Significantly higher mean percent increases from baseline were seen with the estradiol capsule vs placebo for superficial cells (35% vs 4%, P = .0002) and intermediate cells (13% vs 4%, P = .0002) at 2 weeks.

The mean percent decrease from baseline in parabasal cells was significantly greater with the estradiol capsule than with placebo (54% vs 5%, P = .0001), as was the mean decrease in vaginal pH (0.97 vs 0.34, P =.0002).

The estradiol group also had significantly greater improvements in vaginal epithelial integrity and secretions compared with the placebo arm. Vaginal symptom improvement was similar between groups, but this was likely due to the small size and short duration of the study, Dr Pickar said.

That will need to be proven in longer studies, Dr Newton told Medscape Medical News. "The study was short, only 2 weeks. Women didn't notice any difference in their symptoms.... That will be the bottom line. If women take it and don't feel better, they won't keep taking it. These are really early dose-finding studies."

Adverse events, reported by 14 of the 50 women, were relatively mild and included vaginal discharge, dysplasia, or pruritis, vulvovaginal pain or burning, and cervical dysplasia in the capsule group, and paraesthesia, vaginal hemorrhage, or vulvovaginal discomfort in the placebo group. There were no serious adverse events.

Phase 3 studies of VagiCap began in September 2014, investigating doses of 4, 10, and 25 µg.

This study was funded by TherapeuticsMD. Dr Pickar has consulted for that company, as well as for Wyeth/Pfizer, Ausio Pharmaceuticals, Besins Healthcare Sionogi, and Metagenics. Dr Newton, through her institution, once received funding from Otsuka Pharmaceutical Co, Ltd.

North American Menopause Society (NAMS) 2014 Annual Meeting. Abstract S-6 Presented October 16, 2014.

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