Research and Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany.
Pharma Consult, 12161 Berlin, Germany.
Eur J Endocrinol. 2023 Jul 10;188(7):578-591. doi: 10.1093/ejendo/lvad063.
Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been proposed for treatment of endometriosis and polycystic ovary syndrome. Clinical biomarkers of target engagement, which can greatly facilitate drug development, have not yet been described for AKR1C3 inhibitors. Here, we analyzed pharmacodynamic data from a phase 1 study with a new selective AKR1C3 inhibitor, BAY1128688, to identify response biomarkers and assess effects on ovarian function.
In a multiple-ascending-dose placebo-controlled study, 33 postmenopausal women received BAY1128688 (3, 30, or 90 mg once daily or 60 mg twice daily) or placebo for 14 days. Eighteen premenopausal women received 60 mg BAY1128688 once or twice daily for 28 days.
We measured 17 serum steroids by liquid chromatography-tandem mass spectrometry, alongside analysis of pharmacokinetics, menstrual cyclicity, and safety parameters.
In both study populations, we observed substantial, dose-dependent increases in circulating concentrations of the inactive androgen metabolite androsterone and minor increases in circulating etiocholanolone and dihydrotestosterone concentrations. In premenopausal women, androsterone concentrations increased 2.95-fold on average (95% confidence interval: 0.35-3.55) during once- or twice-daily treatment. Note, no concomitant changes in serum 17β-estradiol and progesterone were observed, and menstrual cyclicity and ovarian function were not altered by the treatment.
Serum androsterone was identified as a robust response biomarker for AKR1C3 inhibitor treatment in women. Aldo-keto reductase 1C3 inhibitor administration for 4 weeks did not affect ovarian function.ClinicalTrials.gov Identifier: NCT02434640; EudraCT Number: 2014-005298-36.
醛酮还原酶 1C3（AKR1C3）被认为参与雄激素、孕激素和雌激素的代谢。AKR1C3 抑制剂已被提议用于治疗子宫内膜异位症和多囊卵巢综合征。目前尚未描述 AKR1C3 抑制剂的靶向结合的临床生物标志物，这将极大地促进药物开发。
在一项多剂量安慰剂对照的 1 期研究中，我们分析了新型选择性 AKR1C3 抑制剂 BAY1128688 的药效学数据，以确定反应生物标志物并评估其对卵巢功能的影响。该研究共纳入 33 名绝经后女性，随机接受 BAY1128688（3、30 或 90mg 每日一次或 60mg 每日两次）或安慰剂治疗 14 天。18 名绝经前女性接受 60mg BAY1128688 每日一次或两次治疗 28 天。
在这两个研究人群中，我们都观察到循环中无活性雄激素代谢物雄酮的浓度显著且剂量依赖性增加，以及较小程度的循环表雄酮和二氢睾酮浓度增加。在绝经前女性中，单次或每日两次治疗时，雄酮浓度平均增加 2.95 倍（95%置信区间：0.35-3.55）。需要注意的是，血清 17β-雌二醇和孕酮浓度没有同时变化，且月经周期和卵巢功能不受治疗影响。
血清雄酮被确定为女性 AKR1C3 抑制剂治疗的一种强大反应生物标志物。AKR1C3 抑制剂治疗 4 周不会影响卵巢功能。
NCT02434640；EudraCT 编号：2014-005298-36。
