目的:Aldo-keto还原酶1C3(AKR1C3)被认为与雄激素有关,黄体酮,和雌激素代谢。已提出抑制AKR1C3用于治疗子宫内膜异位症和多囊卵巢综合征。目标参与的临床生物标志物,这可以极大地促进药物开发,尚未描述AKR1C3抑制剂。这里,我们分析了一项新的选择性AKR1C3抑制剂的1期研究的药效学数据,BAY1128688,以确定反应生物标志物并评估对卵巢功能的影响。
方法:在一项多剂量递增的安慰剂对照研究中,33名绝经后妇女接受BAY1128688(3毫克,30毫克,或每天一次90毫克;或每天两次60毫克)或安慰剂14天。18名绝经前妇女每天一次或两次接受60mgBAY1128688,共28天。
方法:我们通过液相色谱-串联质谱法测量了17种血清类固醇,除了药代动力学分析,月经周期和安全参数。
结果:在两个研究人群中,我们观察到了实质性的,无活性的雄激素代谢物雄酮的循环浓度呈剂量依赖性增加,循环中的etiocholanolone和二氢睾酮浓度略有增加。在绝经前的女性中,在每天一次或两次治疗期间,雄酮浓度平均增加2.95倍(95%置信区间:0.35-3.55).Note,未观察到血清17β-雌二醇和孕酮的伴随变化,月经周期和卵巢功能均未因治疗而改变。
结论:血清雄酮被确定为女性AKR1C3抑制剂治疗的稳健反应生物标志物。AKR1C3抑制剂给药4周不影响卵巢功能。
OBJECTIVE: 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.
METHODS: 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.
METHODS: We measured 17 serum steroids by liquid chromatography-tandem mass spectrometry, alongside analysis of pharmacokinetics, menstrual cyclicity, and safety parameters.
RESULTS: 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.
CONCLUSIONS: 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.