Venook A P, Enders Klein C, Fleming G, Hollis D, Leichman C G, Hohl R, Byrd J, Budman D, Villalona M, Marshall J, Rosner G L, Ramirez J, Kastrissios H, Ratain M J
UCSF Cancer Center, University of California at San Francisco, San Francisco, CA 94115-1705, USA.
Ann Oncol. 2003 Dec;14(12):1783-90. doi: 10.1093/annonc/mdg493.
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.
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.
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.
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.
确定肝功能或肾功能不全或既往盆腔放疗（XRT）是否会导致在给予特定剂量伊立替康时毒性增加，并描述伊立替康及其主要代谢产物在肝功能或肾功能不全患者中的药代动力学特征。
适合接受伊立替康治疗、肝功能或肾功能检查异常或既往接受过盆腔放疗的成年患者符合条件。患者被分配到四个治疗队列之一：队列I，天冬氨酸转氨酶（AST）>或=正常上限的3倍且直接胆红素<1.0mg/dl；队列II，直接胆红素1.0 - 7.0mg/dl；队列III，肌酐1.6 - 5.0mg/dl且肝功能正常；队列IV，既往盆腔XRT且肝功能和肾功能正常。从145或225mg/m²的降低剂量开始，每3周给每个队列中的至少三名患者使用伊立替康。对所有患者测量血液中的伊立替康及其代谢产物。
35名患者可评估毒性。队列I中未观察到剂量限制性毒性，尽管仅三名患者接受了治疗且剂量为225mg/m²。直接胆红素升高的患者出现了剂量限制性毒性，尽管起始剂量为145mg/m²。这些患者似乎与接受全剂量伊立替康治疗的正常患者对活性代谢产物SN - 38的暴露相当。肌酐升高的患者或既往接受盆腔放疗的患者在本研究探索的剂量下似乎没有增加的毒性风险。
接受伊立替康治疗的胆红素升高患者毒性风险增加，建议降低剂量。AST、肌酐升高或既往接受盆腔放疗的患者似乎对伊立替康没有增加的敏感性，但数据不足以支持特定的给药建议。
