Pharmacokinetics and preliminary efficacy of two vaginal gel formulations of ultra-low-dose estriol in postmenopausal women

Abstract

Objectives To investigate the pharmacokinetics, safety and preliminary effectiveness of ultra-low-dose estriol vaginal gel formulations (20 μg/g (T1) and 50 μg/g (T2)) compared to Ovestinon® (estriol 500 μg/0.5 g (R)) and placebo in postmenopausal women.

Methods Forty-three volunteers were randomly assigned to received T1, T2, R or placebo once daily for 21 days. Absorption of estriol after single and multiple administration was analyzed. Cytological changes in the vagina, tolerability and safety were also investigated.

Results Thirty-six women were included in the pharmacokinetic analysis. Systemic absorption was lower with test formulations (AUC_0-t: 171.65 ± 80.18 (T1) and 406.75 ± 199.53 (T2) pg/ml × h) than with Ovestinon® (1221.97 ± 549.06 pg/ml × h). Estriol exposure of the test formulations after multiple administration (AUC_ss: 36.33 ± 30.52 (T1) and 73.71 ± 46.86 (T2) pg/ml × h) was significantly lower than after single-dose administration and not significantly different between them. In contrast, the exposure after repeated administration of Ovestinon® was considerable and not statistically different from levels after single administration. All estriol formulations produced similar improvement in the vaginal maturation value, while placebo showed a small and not significant change. Overall safety and acceptability were good.

Conclusions Estriol 20 and 50 μg/g formulations, while showing a comparable capacity for reversing vaginal atrophy, present a highly favorable safety profile, producing a very low systemic absorption of estriol and significantly lower than that of Ovestinon®.

Keywords:

• Vaginal atrophy
• hormone replacement therapy
• estriol
• topical
• pharmacokinetics
• maturation value
• Ovestinon

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Erratum

Acknowledgements

The authors wish to thank the other investigators involved in the study: Dr A. Rusca, Cross Research SA, Mendrisio, Switzerland, and Dr G. Caccia, Ospedale Regionale Beata Vergine, Mendrisio, Switzerland. A special mention also for Dr Ramón Usandizaga, Dra María de la Calle and Dr Ibone Huerta for their critical review and interpretation of the results.

We would like to gratefully acknowledge Cross Research SA for study coordination. Thanks also to Analytisch Biochemisch Laboratorium BV (Switzerland) for estriol analysis and to RCC for cytological smear preparation and reading. This study was funded by Italfarmaco SA, Spain.

Material contained in this manuscript has been presented at the following meetings: 13th World Congress on Menopause, Rome, June 8–11, 2011; 9th Congress of the European Society of Endocrinology, Copenhagen, September 8–11, 2011.

Conflict of interest

Dr Nieto and Dr Moscoso del Prado are employees of Italfarmaco SA. Dr Radicioni and Dr Loperete are employees of Cross Research. Dr Delgado and Dr Estevez have received honoraria as participants in the advisory board of Italfarmaco SA.

Source of funding

Italfarmaco SA.