Pulsed estrogen therapy: pharmacokinetics of intranasal 17-beta-estradiol (S21400) in postmenopausal women and comparison with oral and transdermal formulations

Pharmacokinetics of estradiol and estrone were assessed in postmenopausal women receiving S21400, a novel 17 beta-estradiol formulation administered by nasal route; the results were compared with those obtained with oral and transdermal routes. Thirty six women received three treatments: a specified dose of 17 beta-estradiol (100, 300 or 450 mu g) given once and as 2 doses, 12 h apart, using three parallel dose groups in a randomised, crossover study. Thereafter, a reservoir patch (50 mu g/day of 17 beta-estradiol) or a tablet of 2 mg micronised 17 beta-estradiol were randomly administered. Plasma concentrations of estradiol and estrone were measured by radioimmunoassays. Following intranasal dosing, estradiol was rapidly absorbed with plasma concentrations reaching maximal values (approximately 1400 pg/ml with a single 300 mu g dose) after 10-30 min and returning within 12 h to levels of untreated postmenopausal women. Systemic exposure to estradiol was dose proportional and independent of the treatment regimen. Moreover, the dose of 300 mu g gave an estimated 24 h systemic exposure to exogenous estradiol close to that of the 50 mu g/day reservoir patch or the 2 mg tablet. The mean estrone to estradiol ratio was similar and 4-fold lower than those with the patch and the tablet, respectively. In conclusion, by this new route for estrogen replacement therapy, the nasal route, the pharmacokinetics of estradiol as S21400 were linear and displayed a 'pulsed' kinetic profile, different from those obtained with the usual routes of administration.