Venook A P, Egorin M J, Rosner G L, Hollis D, Mani S, Hawkins M, Byrd J, Hohl R, Budman D, Meropol N J, Ratain M J
University of California San Francisco, San Francisco, CA, USA.
J Clin Oncol. 2000 Jul;18(14):2780-7. doi: 10.1200/JCO.2000.18.14.2780.
To ascertain if hepatic or renal dysfunction leads to increased toxicity at a given dose of gemcitabine and to characterize the pharmacokinetics of gemcitabine and its major metabolite in patients with such dysfunction.
Adults with tumors appropriate for gemcitabine therapy and who had abnormal liver or renal function tests were eligible. Patients were assigned to one of three treatment cohorts: I-AST level less than or equal to two times normal and bilirubin level less than 1.6 mg/dL; II-bilirubin level 1.6 to 7.0 mg/dL; and III-creatinine level 1.6 to 5.0 mg/dL with normal liver function. Doses were explored in at least three patients within each cohort. Gemcitabine and its metabolite were to be measured in the blood in all patients.
Forty patients were assessable for toxicity. Transient transaminase elevations were observed in many patients but were not dose limiting. Patients with AST elevations tolerated gemcitabine without increased toxicity, but patients with elevated bilirubin levels had significant deterioration in liver function after gemcitabine therapy. Patients with elevated creatinine levels had significant toxicity even at reduced doses of gemcitabine, including two instances of severe skin toxicity. There were no apparent pharmacokinetic differences among the three groups or compared with historical controls.
If gemcitabine is used for patients with elevations in AST level, no dose reduction is necessary. Patients with elevated bilirubin levels have an increased risk of hepatic toxicity, and a dose reduction is recommended. Patients with elevated creatinine levels seem to have increased sensitivity to gemcitabine, but the data are not adequate to support a specific dosing recommendation.
确定在给予特定剂量吉西他滨时，肝或肾功能不全是否会导致毒性增加，并描述吉西他滨及其主要代谢产物在此类功能不全患者中的药代动力学特征。
适合吉西他滨治疗且肝功能或肾功能检查异常的成年患者符合条件。患者被分配到三个治疗队列之一：I组——谷草转氨酶（AST）水平小于或等于正常水平的两倍且胆红素水平小于1.6mg/dL；II组——胆红素水平为1.6至7.0mg/dL；III组——肌酐水平为1.6至5.0mg/dL且肝功能正常。每个队列至少在三名患者中探索剂量。所有患者均需检测血液中的吉西他滨及其代谢产物。
40名患者可评估毒性。许多患者观察到短暂的转氨酶升高，但并非剂量限制性。AST升高的患者耐受吉西他滨且毒性未增加，但胆红素水平升高的患者在接受吉西他滨治疗后肝功能显著恶化。肌酐水平升高的患者即使使用降低剂量的吉西他滨也有显著毒性，包括两例严重的皮肤毒性。三组之间或与历史对照相比，没有明显的药代动力学差异。
如果将吉西他滨用于AST水平升高的患者，无需降低剂量。胆红素水平升高的患者肝毒性风险增加，建议降低剂量。肌酐水平升高的患者似乎对吉西他滨的敏感性增加，但数据不足以支持具体的给药建议。
