Single-dose pharmacokinetics and pharmacodynamics assessment of oestriol and trimegestone containing vaginal rings in healthy women with childbearing potential

Abstract

Purpose

To evaluate the pharmacokinetics and pharmacodynamics of oestriol (E3) and trimegestone (TMG) in healthy women after application of three different vaginal rings over 21 days. The vaginal rings had a nominal delivery rate of 0.413/0.050 mg/day (Test 1), 0.311/0.090 mg/day (Test 2) and 0.209/0.137 mg/day (Test 3) E3/TMG.

Methods

Thirty-five healthy women were randomised to receive a single application of Test 1, 2 or 3 (Clinical Trial NCT03343912). The E3 and TMG plasma concentration was determined by LC-MS/MS. Oestradiol (E2) and progesterone (PG) serum concentrations, and bleeding patern were determined as pharmacodynamic parameters. Safety was assessed by evaluation of adverse events and local tolerability.

Results

The total and maximum exposure of E3 and TMG increased in a proportional ratio to dose. However, not in a magnitude which was expected from the dose differences for E3. During Test 2 and 3 treatment all E2 and PG values remained on a well suppressed level until end of treatment. E2 and PG serum levels increased distinctly earlier after ring removal with Test 1 compared to Test 2 and 3. Test 3 achieved 95.24% of “no bleeding” days under treatment followed by Test 1 (91.67%), and Test 2 (86.15%).

Conclusions

The Test 3 formulation presented the best dose combination of E3/TMG for contraception. Moreover, all vaginal rings were well tolerated.

摘要

目的：评估健康女性应用三种不同方案的雌三醇（E3）和曲美孕酮（TMG）阴道环21天后的药代动力学和药效学。阴道环的E3/TMG释放率分别为0.413/0.050 mg/天（方案1）、 0.311/0.090 mg/天（方案2）和0.209/0.137 mg/天（方案3）。

方法：35名健康女性被随机分为方案1、方案2和方案3（临床试验NCT03343912）。采用LC-MS/MS法测定血浆中E3和TMG浓度, 以雌二醇（E2）和孕酮（PG）血清浓度及出血模式作为药效学参数。通过不良事件和局部耐受性评估安全性。

结果：E3和TMG的总暴露量和最大暴露量与剂量成比例增加 。然而其差异并不像E3剂量差异明显。方案2和方案3整个治疗期间, 患者血清E2和PG值保持在良好的被抑制水平。方案1取环后血清E2和PG水平较方案2和3明显提前升高。方案3在治疗期间“无出血”天数达到95.24%的, 其次是方案1（91.67%）和方案2（86.15%）。

结论：方案3是E3/TMG用以避孕的最佳剂量组合, 所有方案的阴道环患者均可耐受。

Keywords:

• Oestriol
• trimegestone
• vaginal ring
• pharmacokinetics
• pharmacodynamics

Disclosure statement

RW and AW are employees of SocraTec R&D. As a clinical research organisation undertaking phase I clinical trials, SocraTec R&D has undertaken projects involving products of other pharmaceutical companies. No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was funded by São Paulo Research Foundation [FAPESP, Grant number 2016/22506-1]; and Evestra GmbH, Germany.