ART-001是一种口服选择性PI3Kα抑制剂，目前正在开发用于慢性静脉畸形（SFVMs）的治疗。ART-001曾用于晚期实体肿瘤的开发，但由于其I期研究中存在显著的药代动力学（PK）变异性而被暂停。本研究采用了Ⅰ期、随机、双盲、安慰剂对照的方法，评估了新开发的干糖浆制剂的安全性、耐受性和ART-001的药代动力学。该制剂旨在优化ART-001的药代动力学特性，并符合儿童人群的用药要求。健康男性成年人接受单剂和重复剂量的ART-001。ART-001在单剂和多剂之后被迅速吸收，曝光随剂量增加而增加。干糖浆制剂显著改善了受试者间PK变异性。食物减少了AUC和最大浓度分别约12%和36%。在重复给药100mg后的第5天，血浆浓度达到了稳态，AUC累积比为1.9。没有死亡或严重不良事件。最常见的不良事件是高血糖。高血糖的所有病例均为轻度至中度且短暂的，无需医疗干预。300mg一日剂量组观察到血清肌酐上升，导致第5天停药。总之，研究表明，ART-001干糖浆制剂的单剂和多剂，分别为最高400和100mg，具有良好的安全性和耐受性，并支持进一步临床开发用于SFVMs的治疗。© 2023 ARTham Therapeutics.由美国临床药理学和治疗学学会委托Wiley Periodicals LLC刊登的《临床和转化科学》。

ART-001 is an orally available selective PI3Kα inhibitor currently being developed for the treatment of slow-flow vascular malformations (SFVMs). ART-001 used to be developed for advanced solid tumors, but was suspended largely due to significant pharmacokinetic (PK) variability in its phase I studies. This phase I, randomized, double-blinded, placebo-controlled study evaluated safety, tolerability and PK of ART-001 with a newly developed dry syrup formulation, which was designed to optimize PK properties of ART-001 and to be compliant with the pediatric population. Single and multiple doses of ART-001 were administered to healthy male adults. ART-001 was rapidly absorbed after the single and repeated doses, and the exposure of ART-001 increased with increased dose. The dry syrup formulation substantially improved the intersubject PK variability. Food decreased area under the concentration-time curve (AUC) and maximum plasma concentration by 12% and 36%, respectively. The plasma concentration had reached a steady-state on day 5 of the repeated doses of 100 mg and AUC accumulation ratio was 1.9. There were no deaths or serious adverse events. The most frequent adverse event was hyperglycemia. All cases of hyperglycemia were mild to moderate and transient, and required no medical interventions. Serum creatinine increase was observed in 300 mg once daily dosing group leading to dose discontinuation on day 5. In conclusion, it was demonstrated that the single doses and repeated doses of the ART-001 dry syrup formulation, at up to 400 and 100 mg, respectively, were safe and tolerated with favorable PK profile, supporting further clinical development for the treatment of SFVMs.© 2023 ARTham Therapeutics. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.