Pharmacokinetics and pharmacodynamics of 3 dosages of oestriol after continuous vaginal ring administration for 21 days in healthy, postmenopausal women

Summary

Aim

Evaluation of the oestriol pharmacokinetics, pharmacodynamics and safety in healthy, postmenopausal women under treatment with a vaginal ring with continuous delivery rates of 0.125 (Test 1), 0.250 (Test 2) or 0.500 mg/day (Test 3) for 21 days.

Methods

Thirty‐one subjects received a single application of Test 1, 2 or 3. The oestriol plasma concentration was determined by LC‐MS/MS. The FSH, LH and SHBG serum concentrations, maturation value (MV) and vaginal pH were assessed to describe the pharmacodynamics. Adverse events, local tolerability and endometrial thickness (ET) were evaluated to determine safety.

Results

The 90% CI of the coefficient/slope β was 0.5997 %‐1.174 % for AUC_0‐tlast, 0.5838 %‐1.115 % for AUC_0‐∞ and 0.2408 %‐0.943 % for C_max. Dose‐proportionality could not be rejected for AUC, but a deviation from proportionality was statistically significant for C_max. The FSH and LH curves showed a decrease that was more pronounced with higher delivery rates; however, SHBG did not presented this behavior. A treatment effect on MV and vaginal pH was comparable for all formulations. All products showed increase in MV (70‐80%) and the distribution of parabasal, intermediate and superficial cells showed a shift towards superficial cells. The vaginal pH values markedly decreased under treatment. The effect on ET was no dose‐dependent.

Conclusion

All formulations released sufficient amounts of oestriol to trigger the maximum local effect. However, there was no difference between formulations regarding surrogate parameters for clinical efficacy. A dose‐dependency; however, was clearly demonstrated for FSH and LH. The product was well tolerated and safe.

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