PDF(Pubmed)
Abstract：
AT-752 is a novel guanosine nucleotide prodrug inhibitor of the dengue virus (DENV) polymerase with sub-micromolar, pan-serotype antiviral activity. This phase 1, double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of ascending single and multiple oral doses of AT-752 in healthy subjects. AT-752 was well tolerated when administered as a single dose up to 1,500 mg or when administered as multiple doses up to 750 mg three times daily (TID). No serious adverse events occurred, and the majority of treatment-emergent adverse events were mild in severity and resolved by the end of the study. In those receiving single ascending doses of AT-752, no pharmacokinetic sensitivity was observed in Asian subjects, and no food effect was observed. Plasma exposure of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, increased with increasing dose levels of AT-752 and exhibited a long half-life of approximately 15-25 h. Administration of AT-752 750 mg TID led to a rapid increase in plasma levels of AT-273 exceeding the target in vitro 90% effective concentration (EC90) of 0.64 µM in inhibiting DENV replication, and maintained this level over the treatment period. The favorable safety and pharmacokinetic results support the evaluation of AT-752 as an antiviral for the treatment of dengue in future clinical studies.Registered at ClinicalTrials.gov (NCT04722627).
摘要：
AT-752是登革热病毒（DENV）聚合酶的一种新型鸟苷核苷酸前药抑制剂，泛血清型抗病毒活性。第一阶段，双盲，安慰剂对照,首次在人研究评估了安全性，耐受性,以及在健康受试者中递增的单次和多次口服剂量AT-752的药代动力学。当以高达1,500mg的单剂量施用或当以高达750mg的多剂量每天三次(TID)施用时,AT-752具有良好的耐受性。无严重不良事件发生,大多数因治疗引起的不良事件严重程度较轻,并在研究结束时得以解决.在接受单次递增剂量AT-752的患者中，在亚洲受试者中未观察到药代动力学敏感性，没有观察到食物效应。鸟苷核苷代谢物AT-273的血浆暴露，该药物的活性三磷酸代谢物的替代品，随着AT-752剂量水平的增加而增加，并显示出约15-25小时的长半衰期。AT-752750mgTID的给药导致AT-273的血浆水平迅速增加，超过了抑制DENV复制的目标体外90％有效浓度（EC90）0.64µM，并在治疗期间保持这一水平。有利的安全性和药代动力学结果支持在未来的临床研究中评估AT-752作为治疗登革热的抗病毒药物。在ClinicalTrials.gov（NCT04722627）注册。
