Goldberg R M, Reid J M, Ames M M, Sloan J A, Rubin J, Erlichman C, Kuffel M J, Fitch T R
Divisions of Medical Oncology, Developmental Oncology Research, and Cancer Statistics, Mayo Clinic, Rochester, Minnesota 55905, USA.
Clin Cancer Res. 1997 Dec;3(12 Pt 1):2363-70.
Fazarabine (1-beta-D-arabinofuranosyl-5-aza-cytosine, or Ara-AC) is a nucleoside analogue that consists of the arabinoside ring of 1-beta-D-arabinofuranosylcytosine and the pyrimidine base of 5-azacytidine. In Phase I and Phase II trials, neutropenia was dose limiting, with minimal nonhematological toxicity. The in vitro cytotoxic concentrations of Ara-AC could not be achieved in these studies; neutropenia precluded dose escalation. The objectives of this study were: to determine either the maximum tolerated dose of Ara-AC or to safely achieve target plasma levels of 2-5 microgram/ml when Ara-AC was administered as a 24-h infusion with granulocyte colony-stimulating factor (G-CSF) to patients with advanced refractory malignancies; to characterize the pharmacokinetic behavior of Ara-AC with G-CSF; and to define the relationship of Ara-AC pharmacokinetics to toxicity. Twenty-four patients received 67 courses of Ara-AC at doses of 54-112 mg/m2/h. Dose-limiting toxicity was approached but not reached. Grade 3 or 4 neutropenia and nausea were the principle side effects. Steady-state plasma concentrations exceeded the minimum target concentration of 2 microgram/ml in all patients who received >/=78 mg/m2/h for 24 h. The maximum target concentration was approached during administration of 112 mg/m2/h for 24 h. The mean steady-state clearance was 475 +/- 103 ml/min/m2 and did not change with dose. One partial response was seen. One patient received 16 courses and another received 7 courses of therapy before progression. Ara-AC can be safely administered in doses that result in plasma concentrations of 2-5 microgram/ml, if it is given with G-CSF. Phase II trials of Ara-AC in selected malignancies are planned.
法扎拉滨（1-β-D-阿拉伯呋喃糖基-5-氮杂胞嘧啶，或Ara-AC）是一种核苷类似物，由1-β-D-阿拉伯呋喃糖基胞嘧啶的阿拉伯糖苷环和5-氮杂胞苷的嘧啶碱基组成。在I期和II期试验中，中性粒细胞减少是剂量限制性毒性，非血液学毒性最小。在这些研究中无法达到Ara-AC的体外细胞毒性浓度；中性粒细胞减少妨碍了剂量递增。本研究的目的是：确定Ara-AC的最大耐受剂量，或在给晚期难治性恶性肿瘤患者静脉输注粒细胞集落刺激因子（G-CSF）24小时的同时，安全达到2 - 5微克/毫升的目标血浆浓度；描述Ara-AC与G-CSF联合应用时的药代动力学行为；确定Ara-AC药代动力学与毒性之间的关系。24例患者接受了67个疗程的Ara-AC治疗，剂量为54 - 112毫克/平方米/小时。接近但未达到剂量限制性毒性。3级或4级中性粒细胞减少和恶心是主要副作用。在所有接受≥78毫克/平方米/小时持续24小时的患者中，稳态血浆浓度超过了2微克/毫升的最低目标浓度。在给予112毫克/平方米/小时持续24小时的过程中接近最大目标浓度。平均稳态清除率为475±103毫升/分钟/平方米，且不随剂量变化。观察到1例部分缓解。1例患者在疾病进展前接受了16个疗程，另1例接受了7个疗程的治疗。如果与G-CSF联合使用，Ara-AC可以安全地以能使血浆浓度达到2 - 5微克/毫升的剂量给药。计划在特定恶性肿瘤中开展Ara-AC的II期试验。
