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Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous
Abstract:
A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m2 per day for 5 days and repeated every 21-28 days. The patient population had a median age of 55 years (range 38-76) and a median Karnofsky performance status of 80 (range 60-100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/microliter (range 100-4800) in 8 heavily pretreated patients treated at 350 mg/m2 per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m2 and had WBC nadirs of 800/microliter and 600/microliter. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m2 per day, nadir 85,000/microliter). Neither hyponatremia nor symptomatic hypo-osmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m2 per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09-6.79 micrograms/ml. Steady state was achieved in 14.5 +/- 5.9 h (mean +/- SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t 1/2 of 5.3 +/- 3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543 +/- 150 micrograms/ml h and reflected a cyclophosphamide total-body clearance (CLTB) of 103 +/- 31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6-4.3 micrograms/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3% +/- 7.6% and 15.1% +/- 2.0% of the administered daily dose, respectively. The t1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m2 as an i.v. bolus.(ABSTRACT TRUNCATED AT 400 WORDS)