Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and leukemia group B 9565

Purpose: To ascertain if hepatic or renal dysfunction leads to increased to xicity at a given dose of gemcitabine and to characterize the pharmacokinet ics of gemcitabine and its major metabolite in patients with such dysfuncti on. Patients and Methods: Adults with tumors appropriate for gemcitabine th erapy and who had abnormal liver or renal function tests were eligible. Pat ients were assigned to one of three treatment cohorts: I-AST level less tha n 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/d L with normal liver function. Doses were explored in at least three patient s within each cohort. Gemcitabine and its metabolite were to be measured in the blood in all patients. Results: Forty patients were assessable for tox icity. 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 ha d significant deterioration in liver function after gemcitabine therapy. Pa tients with elevated creatinine levels had significant toxicity even at red uced 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. Conclusion: If gemcitabine is used fo r patients with elevations in AST level, no dose reduction is necessary. Pa tients with elevated bilirubin levels have an increased risk of hepatic tox icity, and a dose reduction is recommended. Patients with elevated creatini ne levels seem to have increased sensitivity to gemcitabine, but the data a re nat adequate to support a specific dosing recommendation. (C) 2000 by Am erican Society of Clinical Oncology.