Amdizalisib又名HMPL-689，是一种新型选择性强效PI3Kδ抑制剂，目前正在中国进行II期临床开发，用于治疗血液系统恶性肿瘤。 amdizalisib 的临床前药代动力学 (PK) 在体外和体内进行了广泛的表征，以支持 amdizalisib 的进一步开发。我们利用体外实验表征了 amdizalisib 的血浆蛋白结合、血液与血浆分配比、细胞通透性、肝微粒体代谢稳定性和药物相互作用潜力。在单次静脉内或口服 amdizalisib 后，对小鼠、大鼠、狗和猴子进行体内 PK 评估。在大鼠中评估 amdizalisib 的组织分布和排泄。 amdizalisib 在临床前物种（小鼠、大鼠、狗和猴子）中的 PK 参数（CL 和 Vss）用于使用异速生长缩放（AS）方法的人类 PK 预测。 Amdizalisib 吸收良好，在小鼠、大鼠、狗和猴子体内显示出低至中等的清除率。它具有高细胞渗透性，且不具有 P-糖蛋白 (P-gp) 或乳腺癌抗性蛋白 (BCRP) 底物的能力。 amdizalisib 的血浆蛋白结合率很高（约 90%）。它分布广泛，但在大鼠中脑与血浆的暴露比率较低。 Amdizalisib在体内广泛代谢，原型药在排泄物中的回收率较低。 Amdizalisib 和/或其代谢物主要通过大鼠的胆汁和尿液排泄。 Amdizalisib 对 P-gp 显示出抑制潜力，但对 BCRP 没有抑制作用，并观察到抑制 CYP2C8 和 CYP2C9，IC50 值分别为 30.4 和 10.7 μM。它对 CYP1A2、CYP2B6、CYP3A4 和 CYP2C9 表现出诱导潜力。这些 ADME 研究的临床前数据表明 amdizalisib 具有良好的药代动力学特征，预计将支持 amdizalisib 作为有前景的抗癌药物的未来临床开发。版权所有 © 2024 Jiang、Li、Xue、Xia、Wang、Sai、Dai和苏。

Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological malignancies. The preclinical pharmacokinetics (PK) of amdizalisib were extensively characterized in vitro and in vivo to support the further development of amdizalisib. We characterized the plasma protein binding, blood-to-plasma partition ratio, cell permeability, hepatic microsomal metabolic stability, and drug-drug interaction potential of amdizalisib using in vitro experiments. In vivo PK assessment was undertaken in mice, rats, dogs, and monkeys following a single intravenous or oral administration of amdizalisib. The tissue distribution and excretion of amdizalisib were evaluated in rats. The PK parameters (CL and Vss) of amdizalisib in preclinical species (mice, rats, dogs, and monkeys) were utilized for the human PK projection using the allometric scaling (AS) approach. Amdizalisib was well absorbed and showed low-to-moderate clearance in mice, rats, dogs, and monkeys. It had high cell permeability without P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrate liability. Plasma protein binding of amdizalisib was high (approximately 90%). It was extensively distributed but with a low brain-to-plasma exposure ratio in rats. Amdizalisib was extensively metabolized in vivo, and the recovery rate of the prototype drug was low in the excreta. Amdizalisib and/or its metabolites were primarily excreted via the bile and urine in rats. Amdizalisib showed inhibition potential on P-gp but not on BCRP and was observed to inhibit CYP2C8 and CYP2C9 with IC50 values of 30.4 and 10.7 μM, respectively. It exhibited induction potential on CYP1A2, CYP2B6, CYP3A4, and CYP2C9. The preclinical data from these ADME studies demonstrate a favorable pharmacokinetic profile for amdizalisib, which is expected to support the future clinical development of amdizalisib as a promising anti-cancer agent.Copyright © 2024 Jiang, Li, Xue, Xia, Wang, Sai, Dai and Su.