Shengfu Wang1,2, Chunyan Wang3,4, Xiao Wang3,4, Xiang Wang1,2, Lina Huang1,2, Jiajie Kuai1,2, Wei Wei1,2, Xiaorong Lu5,6, Shangxue Yan7,8. 1. Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China. 2. 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. 3. Hefei Blooming Drug Safety Evaluation Co., Ltd, 358 Ganquan Road, Hefei, 230031, China. 4. Anhui Province Key Laboratory of Druggability Evaluation for New Drugs, 358 Ganquan Road, Hefei, 230031, China. 5. Hefei Blooming Drug Safety Evaluation Co., Ltd, 358 Ganquan Road, Hefei, 230031, China. luxr2009@163.com. 6. Anhui Province Key Laboratory of Druggability Evaluation for New Drugs, 358 Ganquan Road, Hefei, 230031, China. luxr2009@163.com. 7. Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China. yan-shx@163.com. 8. 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. yan-shx@163.com.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: HYGT-110 exhibited a low oral bioavailability (10.91%) in KM mice. Compared with HYGT-110 treatment, the Cmax and AUC0-t 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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. RESULTS: HYGT-110 exhibited a low oral bioavailability (10.91%) in KM mice. Compared with HYGT-110 treatment, the Cmax and AUC0-t 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. CONCLUSIONS: 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.
Authors: H Derendorf; L J Lesko; P Chaikin; W A Colburn; P Lee; R Miller; R Powell; G Rhodes; D Stanski; J Venitz Journal: J Clin Pharmacol Date: 2000-12 Impact factor: 3.126
Authors: Suzanne George; Qian Wang; Michael C Heinrich; Christopher L Corless; Meijun Zhu; James E Butrynski; Jeffrey A Morgan; Andrew J Wagner; Edwin Choy; William D Tap; Jeffrey T Yap; Annick D Van den Abbeele; Judith B Manola; Sarah M Solomon; Jonathan A Fletcher; Margaret von Mehren; George D Demetri Journal: J Clin Oncol Date: 2012-05-21 Impact factor: 44.544
Authors: S Hirota; K Isozaki; Y Moriyama; K Hashimoto; T Nishida; S Ishiguro; K Kawano; M Hanada; A Kurata; M Takeda; G Muhammad Tunio; Y Matsuzawa; Y Kanakura; Y Shinomura; Y Kitamura Journal: Science Date: 1998-01-23 Impact factor: 47.728