"目录号: HY-13631A
Cell Cycle/DNA Damage-
Exatecan(DX-8951)甲磺酸盐是拓扑异构酶I抑制剂喜树碱的合成类似物，增加了其水溶性和抗肿瘤活性，降低了毒性。
Topoisomerase
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生物活性
Description
Exatecan Mesylate (DX-8951) is a totally synthetic analogue of the topoisomerase I-inhibitor camptothecin, which was synthesised to impart increased aqueous solubility, greater tumour efficacy, and less toxicity than camptothecin itself.IC50 value:Target: topoisomerase IExatecan was given as i.v. infusion over 30 min at a dose of 0.5mg/m2 every day for five consecutive days, repeated every 21 days. Seventy-four percentage of cycles could be given without dose or schedule modification. The main toxicity was haematotoxicity with grade 3/4 neutropenia in 49%, grade 3/4 thrombocytopenia in 23%, and grade 3/4 anaemia in 15% of patients, respectively [1]. The most common drug-related toxicity was neutropenia. Non-hematologic toxicities were mostly mild to moderate; the most common were nausea, vomiting and anorexia. Plasma concentrations of DX-8951 (the anhydrous form of DX-8951f) were well described using a linear 2-compartment PK model. All concentrations and dose events were simultaneously modeled and explained by the population PK model. There was no evidence of non-linearity in the elimination PK, auto-inhibition or induction of DX-8951 clearance over the five days of administration [2]. Thirty-one patients were treated with 100 courses of exatecan at 6 dose-schedule levels. The incidence of the principal dose-limiting toxicities, neutropenia and thrombocytopenia, was unacceptably high at exatecan doses exceeding 0.15 mg/m(2)/day as a 21-day CIVI, which was determined to be the MTD for both MP and HP patients [3].
Clinical Trial
NCT00041236
European Organisation for Research and Treatment of Cancer - EORTC
Sarcoma
May 2002
Phase 2
NCT00045318
Jonsson Comprehensive Cancer Center-National Cancer Institute (NCI)
Unspecified Adult Solid Tumor, Protocol Specific
May 2002
Phase 1
NCT00055939
Daiichi Sankyo Inc.
Sarcoma
January 2003
Phase 2
NCT00055952
Daiichi Sankyo Inc.
Sarcoma
January 2003
Phase 2
NCT00017212
Daiichi Sankyo Inc.
Esophageal Cancer-Gastric Cancer
April 2001
Phase 2
NCT00023972
Daiichi Sankyo Inc.
Pancreatic Cancer
July 2001
Phase 3
NCT00004108
Daiichi Sankyo Inc.
Liver Cancer
September 1999
Phase 2
NCT00005938
Daiichi Sankyo Inc.
Extrahepatic Bile Duct Cancer-Gallbladder Cancer-Liver Cancer
March 2000
Phase 2
NCT00004866
Daiichi Sankyo Inc.
Cervical Cancer
January 2000
Phase 2
NCT00005091
Daiichi Pharmaceuticals-National Cancer Institute (NCI)
Lung Cancer
February 1999
Phase 2
NCT00003951
Daiichi Sankyo Inc.
Pancreatic Cancer
June 1999
Phase 2
NCT00004212
Daiichi Sankyo Inc.
Brain and Central Nervous System Tumors-Lymphoma-Unspecified Childhood Solid Tumor, Protocol Specific
September 1999
Phase 1
NCT00004045
Daiichi Sankyo Inc.
Prostate Cancer
June 1999
Phase 2
NCT00004046
Daiichi Sankyo Inc.
Breast Cancer
June 1999
Phase 2
NCT00004047
Daiichi Sankyo Inc.
Leukemia-Myelodysplastic Syndromes
June 1999
Phase 1
NCT00004060
Daiichi Sankyo Inc.
Fallopian Tube Cancer-Ovarian Cancer-Primary Peritoneal Cavity Cancer
July 1999
Phase 2
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References
[1].Reichardt P, et al. Exatecan in pretreated adult patients with advanced soft tissue sarcoma: results of a phase II--study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2007 Apr;43(6):1017-22.
[2].Ajani JA, et al. A phase II clinical and pharmacokinetic study of intravenous exatecan mesylate (DX-8951f) in patients with untreated metastatic gastric cancer. Invest New Drugs. 2005 Oct;23(5):479-84.
[3].Garrison MA, et al. A Phase I and pharmocokinetic study of exatecan mesylate administered as a protracted 21-day infusion in patients with advanced solid malignancies. Clin Cancer Res. 2003 Jul;9(7):2527-37.