Phase I pharmacokinetic and pharmacogenomic study of E7070 administered once every 21 days.
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.
Yamada
Yasuhide
Y
Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. yayamada@ncc.go.jp
Yamamoto
Noboru
N
Shimoyama
Tatsu
T
Horiike
Atsushi
A
Fujisaka
Yasuhito
Y
Takayama
Kyoko
K
Sakamoto
Terumi
T
Nishioka
Yuki
Y
Yasuda
Sanae
S
Tamura
Tomohide
T
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D011110:Polymorphism, Genetic; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*
C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19