Exatecan Mesylate

"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.

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