目的:为了描述人类首次研究的结果,一种研究性口服选择性MC1R激动剂,正在开发用于治疗红细胞生成原卟啉症(EPP)和X连锁原卟啉症(XLP)。
方法:在这种双盲中,安慰剂对照1期研究,安全,耐受性,药代动力学,并评估了健康参与者单次和多次递增口服剂量的药物动力学。
结果:Dersimelagon在健康参与者中总体耐受性良好,最常见的TEAE是多剂量后的扁豆(52.8%)和皮肤色素沉着过度(50.0%)。在1-至600-mg单剂量范围内,血浆中的全身暴露量(基于AUC0-∞和Cmax)以略高于剂量比例的方式增加。多次剂量后,dersimelagon迅速吸收(中位Tmax在第1天和第14天的给药后4至5小时范围内)。平均t1/2在第14天的范围为10.56至18.97h,并且血浆浓度的稳定状态通常通过多次给药5天达到。年龄或种族对德西姆龙或其代谢产物德西姆龙葡糖苷酸的PK谱没有可观察到的影响。单剂量的dersimelagon未观察到对黑色素密度(MD)的治疗相关影响;然而,在多次剂量后,在接受150和300mgdersimelagon的参与者中观察到MD增加.
结论:我们的研究结果表明,dersimelagon通常具有良好的耐受性,并且在不同的亚组中表现出基本一致的PK谱。与治疗相关的MD增加需要在更大的研究人群以及EPP和XLP患者中进行进一步研究。
背景:一项调查安全性的研究,MT-7117在健康受试者中的耐受性和药代动力学,NCT02834442,https://clinicaltrials.gov/ct2/show/NCT02834442,2016年7月开始注册。
OBJECTIVE: To describe outcomes from the first-in-human study of dersimelagon, an investigational oral selective MC1R agonist, under development for the treatment of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP).
METHODS: In this double-blind, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of dersimelagon in healthy participants were evaluated.
RESULTS: Dersimelagon was generally well tolerated in healthy participants, with the most common TEAEs being lentigo (52.8%) and skin hyperpigmentation (50.0%) after multiple doses. Systemic exposure to dersimelagon in plasma (based on AUC0-∞ and Cmax) increased in a slightly more than dose-proportional manner over the 1- to 600-mg single-dose range. Following multiple doses, dersimelagon was rapidly absorbed (median Tmax ranging from 4 to 5 h postdose on days 1 and 14). Mean t1/2 ranged from 10.56 to 18.97 h on day 14, and the steady state of plasma concentration was generally reached by 5 days of multiple dosing. There were no observable effects of age or race on the PK profile of dersimelagon or its metabolite dersimelagon glucuronide. No treatment-related effects on melanin density (MD) were observed following single doses of dersimelagon; however, after multiple doses, increases in MD were observed in participants receiving 150 and 300 mg dersimelagon.
CONCLUSIONS: Our study results indicate that dersimelagon is generally well tolerated and demonstrates a generally consistent PK profile across diverse subgroups. Treatment-related increases in MD warrant further investigation in a larger study population and in patients with EPP and XLP.
BACKGROUND: A Study to Investigate the Safety, Tolerability and Pharmacokinetics of MT-7117 in Healthy Subjects, NCT02834442, https://clinicaltrials.gov/ct2/show/NCT02834442 , registration began July 2016.