背景:BAY1128688是aldo-keto还原酶家族1成员C3(AKR1C3)的选择性抑制剂,一种与子宫内膜异位症和其他疾病病理有关的酶。体内动物研究表明BAY1128688在治疗子宫内膜异位症中的潜在治疗应用。健康志愿者的早期临床研究支持IIa期的开始。
目的:本手稿报告了一项临床试验(AKRENDO1)的结果,该试验评估了BAY1128688对患有子宫内膜异位症相关疼痛症状的绝经前成年女性在12周治疗期间的影响。
方法:该安慰剂对照的参与者,多中心IIa期临床试验(NCT03373422)随机分为五个BAY1128688治疗组之一:3mg,每日一次(OD),10mgOD,30mgOD,30毫克,每日两次(BID),60毫克BID;或安慰剂组。功效,安全,并对BAY1128688的耐受性进行了研究。
结果:在BAY1128688治疗后观察到剂量/暴露依赖性肝毒性,其特征是在治疗约12周时出现血清丙氨酸转移酶(ALT)升高,并促使试验提前终止。有效试验完成者数量的减少排除了关于治疗功效的结论。BAY1128688在子宫内膜异位症参与者中的药代动力学和药效学与先前在健康志愿者中发现的那些相当,并且不能预测随后观察到的ALT升高。
结论:在AKRENDO1中观察到的BAY1128688的肝毒性不能通过动物研究或健康志愿者的研究来预测。然而,BAY1128688与胆盐转运蛋白的体外相互作用表明在较高剂量下存在肝毒性的潜在危险因素.这突出了体外机制和转运蛋白相互作用研究在评估肝毒性风险中的重要性,并表明需要进一步的机制理解。
背景:NCT03373422(注册日期:2017年11月23日)。
BACKGROUND: BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa.
OBJECTIVE: This manuscript reports the results of a clinical
trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period.
METHODS: Participants in this placebo-controlled, multicenter phase IIa clinical
trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated.
RESULTS: Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature
trial termination. The reduced number of valid
trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed.
CONCLUSIONS: The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required.
BACKGROUND: NCT03373422 (date registered: November 23, 2017).