title: A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863.
abstract: BACKGROUND
  To ascertain if hepatic or renal dysfunction or prior pelvic radiation (XRT) leads to increased toxicity at a given dose of irinotecan and to characterize the pharmacokinetics of irinotecan and its major metabolites in patients with hepatic or renal dysfunction.
  
  
  METHODS
  Adults with tumors appropriate for irinotecan therapy and who had abnormal liver or renal function tests or had prior radiation to the pelvis were eligible. Patients were assigned to one of four treatment cohorts: I, aspartate aminotransferase (AST) > or = 3x upper limit of normal and direct bilirubin <1.0 mg/dl; II, direct bilirubin 1.0-7.0 mg/dl; III, creatinine 1.6-5.0 mg/dl with normal liver function; IV, prior pelvic XRT with normal liver and renal function. Starting with reduced doses of either 145 or 225 mg/m(2), irinotecan was administered every 3 weeks to at least three patients within each cohort. Irinotecan and its metabolites in the blood were measured in all patients.
  
  
  RESULTS
  Thirty-five patients were evaluable for toxicity. No dose-limiting toxicity was seen in cohort I, although only three patients were treated and at a dose of 225 mg/m(2). Patients with elevations of direct bilirubin had dose-limiting toxicities, even though the starting dose was 145 mg/m(2). These same patients appeared to have comparable exposure to the active metabolite SN-38 as normal patients treated with full-dose irinotecan. Patients with elevations of creatinine or with prior pelvic radiotherapy did not appear to have increased risk of toxicity at the doses explored in this study.
  
  
  CONCLUSIONS
  Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.
authors: UCSF Cancer Center, University of California at San Francisco, San Francisco, CA 94115-1705, USA. venook@cc.ucsf.edu
authors: A P
authors: AP
authors: Venook
authors: C
authors: C
authors: Enders Klein
authors: G
authors: G
authors: Fleming
authors: D
authors: D
authors: Hollis
authors: C G
authors: CG
authors: Leichman
authors: R
authors: R
authors: Hohl
authors: J
authors: J
authors: Byrd
authors: D
authors: D
authors: Budman
authors: M
authors: M
authors: Villalona
authors: J
authors: J
authors: Marshall
authors: G L
authors: GL
authors: Rosner
authors: J
authors: J
authors: Ramirez
authors: H
authors: H
authors: Kastrissios
authors: M J
authors: MJ
authors: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D007674:Kidney Diseases / Q000150:complications*; D008107:Liver Diseases / Q000150:complications*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010388:Pelvis / Q000528:radiation effects; D011878:Radiotherapy
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin