Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China.
Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education; Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, 81 Meishan Road, Hefei, 230032, China.
Cancer Chemother Pharmacol. 2021 Nov;88(5):795-804. doi: 10.1007/s00280-021-04332-z. Epub 2021 Jul 26.
CHMFL-KIT-110, a selective c-KIT kinase inhibitor for gastrointestinal stromal tumors (GISTs), possesses a poorly water-soluble, limiting the further development of the drug. This study was to investigate the antitumor efficacy of CHMFL-KIT-110 and CHMFL-KIT-110 solid dispersion (laboratory code: HYGT-110 SD) in GIST tumor xenograft models and to explore the PK/PD relationship of HYGT-110 SD.
Plasma concentrations of HYGT-110 and HYGT-110 SD were determined by LC-MS/MS in KM mice. Antitumor activity was evaluated by measuring tumor volume and weight in c-KIT-dependent GIST xenograft models. PK/PD relationship was assessed by LC-MS/MS and Western Blot in the GIST-T1 xenografted mice.
HYGT-110 exhibited a low oral bioavailability (10.91%) in KM mice. Compared with HYGT-110 treatment, the C and AUC of HYGT-110 SD in mice plasma were substantially increased by 18.81 and 6.76-fold, respectively. HYGT-110 SD (10, 30, and 100 mg/kg/day) also could dose-dependently decrease the tumor volume and weight in the GIST-882 cell-inoculated xenograft mouse models and show 86.35% tumor growth inhibition (TGI) at 28 days at a 25 mg/kg bid dosage in the GIST-T1 cell-inoculated xenograft mouse model. The free concentration of HYGT-110 in plasma was closely correlated with the inhibition of c-KIT phosphorylation levels in tumor tissues.
In comparison with the HPMC formulation, both improved PK and PD characteristics of the solid dispersion formulation of CHMFL-KIT-110 were observed in in vivo animal experiments.
CHMFL-KIT-110 是一种用于治疗胃肠道间质瘤（GIST）的选择性 c-KIT 激酶抑制剂，其水溶性差，限制了药物的进一步开发。本研究旨在探讨 CHMFL-KIT-110 和 CHMFL-KIT-110 固体分散体（实验室代码：HYGT-110 SD）在 GIST 肿瘤异种移植模型中的抗肿瘤疗效，并探讨 HYGT-110 SD 的 PK/PD 关系。
采用 LC-MS/MS 法测定 KM 小鼠体内 HYGT-110 和 HYGT-110 SD 的血药浓度。在 c-KIT 依赖性 GIST 异种移植模型中，通过测量肿瘤体积和重量来评价抗肿瘤活性。采用 LC-MS/MS 和 Western Blot 法评估 GIST-T1 移植瘤小鼠的 PK/PD 关系。
HYGT-110 在 KM 小鼠中的口服生物利用度较低（10.91%）。与 HYGT-110 组相比，HYGT-110 SD 组小鼠血浆中的 C 和 AUC 分别显著增加了 18.81 倍和 6.76 倍。HYGT-110 SD（10、30 和 100mg/kg/天）还能剂量依赖性地降低 GIST-882 细胞接种的异种移植瘤小鼠模型中的肿瘤体积和重量，在 GIST-T1 细胞接种的异种移植瘤小鼠模型中，25mg/kg/天 bid 剂量时可达到 86.35%的肿瘤生长抑制（TGI）。血浆中 HYGT-110 的游离浓度与肿瘤组织中 c-KIT 磷酸化水平的抑制密切相关。
与 HPMC 制剂相比，CHMFL-KIT-110 的固体分散体制剂在体内动物实验中表现出改善的 PK 和 PD 特征。
