title: Relationship between the pharmacokinetics of irinotecan and diarrhea during combination chemotherapy with cisplatin.
abstract: Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 60 mg/m2. The other 13 patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 80 mg/m2 with the granulocyte colony-stimulating factor support (2 micrograms/kg x 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 was 90 mg/m2 in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3-4 diarrhea than those with a lower SN-38 level (P = 0.0003). Stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea (P = 0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin.
authors.affiliation: Department of Internal Medicine, Osaka Prefectural Habikino Hospital.
authors.forename: S
authors.initials: S
authors.lastname: Kudoh
authors.forename: M
authors.initials: M
authors.lastname: Fukuoka
authors.forename: N
authors.initials: N
authors.lastname: Masuda
authors.forename: A
authors.initials: A
authors.lastname: Yoshikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Kusunoki
authors.forename: K
authors.initials: K
authors.lastname: Matsui
authors.forename: S
authors.initials: S
authors.lastname: Negoro
authors.forename: N
authors.initials: N
authors.lastname: Takifuji
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.forename: T
authors.initials: T
authors.lastname: Hirashima
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D003967:Diarrhea / Q000139:chemically induced* / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin