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描述雌莫司汀经阴道环在食蟹猴体内的作用。

Characterization of anastrozole effects, delivered by an intravaginal ring in cynomolgus monkeys.

机构信息

Bayer Healthcare Pharmaceuticals, GDD Research Pharmacokinetics, Müllerstraße 178, 13353 Berlin, Germany.

Bayer Healthcare Pharmaceuticals, GDD Global Chemical & Pharmac. Development, Bayer Oy, PO Box 415, FI-20101 Turku, Finland.

出版信息

Hum Reprod. 2015 Feb;30(2):308-14. doi: 10.1093/humrep/deu315. Epub 2014 Nov 28.

Abstract

STUDY QUESTION

Is it feasible to deliver anastrozole (ATZ), an aromatase inhibitor (AI), by a vaginal polymer-based drug delivery system in the cynomolgus monkey (Macaca fascicularis) to describe the pharmacokinetic profile?

SUMMARY ANSWER

The present study showed the effective release of ATZ into the systemic circulation from intravaginal rings in cynomolgus monkeys.

WHAT IS KNOWN ALREADY

ATZ is a marketed drug with well documented pharmacological and safety profiles for oral administration. Aromatase is the key enzyme catalyzing estrogen biosynthesis and is overexpressed in endometriotic lesions. AIs show therapeutic efficacy in endometriosis in exploratory clinical trials.

STUDY DESIGN, SIZE, DURATION: The pharmacokinetics of the in vivo release and the pharmacodynamic activity of ATZ released by intravaginal rings (IVR) were investigated in healthy cycling female cynomolgus monkeys in three different dose groups (n = 5) for one menstrual cycle.

PARTICIPANTS/MATERIALS, SETTING, METHODS: IVRs for the cynomolgus monkey, releasing three different doses of ATZ were designed and tested for in vitro/in vivo release for up to 42 days. For pharmacokinetic and pharmacodynamic evaluation, plasma samples were taken once daily from Day 1 to 3 and then every third day until menses occurred (17-42 days).

MAIN RESULTS AND THE ROLE OF CHANCE

ATZ was shown to be compatible with the IVR drug delivery system. An average in vivo release of 277 µg/day/animal of ATZ for one menstrual cycle was effective in causing a decrease of systemic estradiol (E₂) levels by ∼30% without inducing counter regulation such as the elevation of FSH or the formation of ovarian cysts.

LIMITATIONS, REASONS FOR CAUTION: The study was limited to three dose groups in which only the highest dose decreased the E₂ level. Hence, additional research with IVRs releasing higher amounts of ATZ is required to define the threshold for an ATZ-dependent ovarian stimulation in cynomolgus monkeys.

WIDER IMPLICATIONS OF THE FINDINGS

The release rate administered from IVRs is sufficient and in a range that supports feasibility of IVR administration of ATZ as a new approach for long-term therapy of estrogen-dependent diseases such as endometriosis in human.

摘要

研究问题

通过阴道聚合物药物输送系统向食蟹猴(Macaca fascicularis)给予芳香酶抑制剂(AIs)阿那曲唑(ATZ)是否可行,以描述药代动力学特征?

总结答案

本研究表明,阴道环内 ATZ 可有效释放到系统循环中。

已知情况

ATZ 是一种已上市药物,其口服给药的药理学和安全性特征已有充分记录。芳香酶是催化雌激素生物合成的关键酶,在子宫内膜异位症病变中过度表达。AIs 在探索性临床试验中显示出对子宫内膜异位症的治疗功效。

研究设计、规模、持续时间:在三个不同剂量组(n = 5)的健康发情周期雌性食蟹猴中,研究了阴道环(IVR)体内释放的药代动力学和 ATZ 释放的药效学活性,持续一个月经周期。

参与者/材料、设置、方法:为食蟹猴设计并测试了用于 IVR 的三种不同剂量的 ATZ,体外/体内释放时间长达 42 天。为了进行药代动力学和药效学评估,从第 1 天到第 3 天每天采集一次血浆样本,然后每三天采集一次,直到发生月经(第 17-42 天)。

主要结果和机会的作用

ATZ 与 IVR 药物输送系统相容。一个月经周期内,每天向动物体内释放 277µg 的 ATZ,可有效降低全身雌二醇(E₂)水平约 30%,而不会引起诸如促卵泡激素(FSH)升高或卵巢囊肿形成等反调节。

局限性、谨慎的原因:该研究仅限于三个剂量组,其中只有最高剂量降低了 E₂ 水平。因此,需要使用释放更多 ATZ 的 IVR 进行额外研究,以确定食蟹猴中 ATZ 依赖性卵巢刺激的阈值。

研究结果的更广泛意义

从 IVR 给予的释放率是足够的,并且在支持将 ATZ 的 IVR 给药作为治疗雌激素依赖性疾病(如人类子宫内膜异位症)的长期治疗新方法的范围内。

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