Document Detail


Phase I pharmacokinetic and pharmacogenomic study of E7070 administered once every 21 days.
MedLine Citation:
PMID:  16232205     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
E7070 is a novel sulfonamide anticancer agent that disrupts the G1/S phase of the cell cycle. The objectives of this phase I study of E7070 were to estimate the maximal tolerated dose (MTD), to determine the recommended dose for phase II, and to clarify the pharmacokinetic profile of E7070 and its relation to polymorphisms of CYP2C9 (*2, *3) and CYP2C19 (*2, *3) in Japanese patients. Patients received 1-2-h i.v. infusions of E7070 (400, 600, 700, 800 or 900 mg/m2) on day 1 of a 21-day cycle. Twenty-one patients received between one and eight cycles of E7070. The dose-limiting toxicities (DLT) comprised leukopenia, neutropenia, thrombocytopenia, elevation of aspartate aminotransferase, colitis, and ileus. The mean area under the plasma concentration-time curve (AUC) for successive dose levels increased in a non-dose-proportional manner. Two patients were heterozygous for the CYP2C9 mutation. For CYP2C19, eight patients were wild type and the remainder had heterozygous (n = 8) or homozygous mutations (n = 5). Regarding the CYP2C19 genotype, the AUC of patients with mutant alleles were higher than those of patients with wild type at a dose of 600 mg/m2 or more. The severity of toxic effects, such as myelosuppression, seemed to depend on the AUC. No partial responses were observed. One patient treated at a dose of 700 mg/m2 experienced a maximum tumor volume reduction of 22.5%. The MTD was estimated to be 900 mg/m2. A dose of 800 mg/m2 is recommended for further phase II studies. The pharmacokinetic/pharmacodynamic properties of E7070 seemed to be influenced by CYP2C19 genotype. The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in monotherapy or in combination chemotherapy.
Authors:
Yasuhide Yamada; Noboru Yamamoto; Tatsu Shimoyama; Atsushi Horiike; Yasuhito Fujisaka; Kyoko Takayama; Terumi Sakamoto; Yuki Nishioka; Sanae Yasuda; Tomohide Tamura
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Publication Detail:
Type:  Clinical Trial, Phase I; Journal Article    
Journal Detail:
Title:  Cancer science     Volume:  96     ISSN:  1347-9032     ISO Abbreviation:  Cancer Sci.     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-10-19     Completed Date:  2005-11-29     Revised Date:  2006-04-27    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  721-8     Citation Subset:  IM    
Affiliation:
Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. yayamada@ncc.go.jp
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Area Under Curve
Aryl Hydrocarbon Hydroxylases / genetics,  metabolism
Drug Administration Schedule
Female
Genotype
Humans
Infusions, Intravenous
Male
Maximum Tolerated Dose
Middle Aged
Mixed Function Oxygenases / genetics,  metabolism
Neoplasms / drug therapy
Polymorphism, Genetic
Sulfonamides / administration & dosage,  adverse effects,  pharmacokinetics*,  pharmacology*
Chemical
Reg. No./Substance:
0/N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; 0/Sulfonamides; EC 1.-/Mixed Function Oxygenases; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C19 protein, human; EC 1.14.14.1/CYP2C9 protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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