title: Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms.
abstract: Previous reports of the influence of UGT1A1 gene polymorphisms on the pharmacokinetics of irinotecan metabolism have not assessed Asian patients treated with FOLFIRI plus bevacizumab for advanced and recurrent colorectal cancer. Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI (bolus irinotecan, folinic acid, and fluorouracil followed by 46-hour fluorouracil infusion) followed by bevacizumab (5 mg/kg) in Cycle 1. In Cycle 2, patients received bevacizumab followed by FOLFIRI. The regimen was in 2-week cycles. The area under-the-curves ratio (AUC0-last) (Cycle 2/Cycle 1) was determined from plasma concentrations of irinotecan and metabolites (SN-38, SN-38G). Safety, efficacy, and drug-drug interactions were analyzed. Median observation period was 7.8 months; median number of cycles 15. Drug-drug interactions were evaluated in eight patients without irinotecan dose reduction. Mean AUC0-last ratios (with/without bevacizumab) of irinotecan, SN-38, and SN-38G were 0.959, 0.927, and 0.931 respectively. Response rate was 65%; median progression-free survival 16.4 months. Response occurred in four patients with, and nine without, UGT1A1 polymorphism. No significant differences occurred between efficacy, safety, or polymorphism status. This cohort showed no differences in safety or efficacy compared to previous reports. Bevacizumab did not affect the pharmacokinetics of irinotecan and its metabolites, irrespective of UGT1A1 polymorphism status.
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan.
authors.forename: Mitsukuni
authors.initials: M
authors.lastname: Suenaga
authors.affiliation: National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Fuse
authors.affiliation: Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Department of Medical Oncology, Tochigi Cancer Center, Utsunomiya, Tochigi, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamanaka
authors.affiliation: Department of Medical Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Motomura
authors.affiliation: Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Department of Medical Oncology, Tochigi Cancer Center, Utsunomiya, Tochigi, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hamamoto
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Mizunuma
authors.affiliation: National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan.
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
authors.affiliation: Clinical Development Division, Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Iwasaki
authors.affiliation: National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
mesh_terms: D000328:Adult; D000368:Aged; D000855:Anorexia / Q000139:chemically induced; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics*; D000068258:Bevacizumab; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D003967:Diarrhea / Q000139:chemically induced; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D002955:Leucovorin; D000099148:UGT1A1 Enzyme
keywords: FOLFIRI; UGT1A1; bevacizumab; colorectal cancer