Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.
Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.
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发表时间：
2002-05
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通讯作者：
N. Ibrahim;N. Desai;S. Legha;P. Soon-Shiong;R. Theriault;E. Rivera;B. Esmaeli;S. Ring;A. Bedikian;G. Hortobagyi;J. Ellerhorst
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作者：
N. Ibrahim;N. Desai;S. Legha;P. Soon-Shiong;R. Theriault;E. Rivera;B. Esmaeli;S. Ring;A. Bedikian;G. Hortobagyi;J. Ellerhorst
ABI-007是一种新型的不含cremopor、蛋白质稳定的纳米紫杉醇制剂。由于不含cremoophor EL，因此ABI-007无需常规预防过敏反应的预用药即可使用。此外，这种新配方允许更高的紫杉醇浓度在溶液中，因此，减少输注体积和时间。这项I期研究检查了ABI-007的毒性、最大耐受剂量（MTD）和药代动力学。实验设计ABI-007在门诊使用，在没有预用药的情况下进行30分钟的输注。ABI-007的剂量范围为135（0级）至375 mg/m2（3级）。16名患者参加了药代动力学研究。结果19例患者得到治疗。输注期间未见急性超敏反应。血液学毒性轻微，无累积性。3级（375 mg/m2）治疗的6例患者中有3例发生剂量限制性毒性，包括感觉神经病变（3例）、口炎（2例）和浅表性角膜病变（2例）。因此，MTD被确定为300毫克/平方米（2级）。药代动力学分析显示紫杉醇C（max）和曲线下面积（inf）值在ABI-007剂量范围135 ~ 300 mg/m2内呈线性增加。个体患者的C（max）和曲线下面积（inf）值与毒性有很好的相关性。结论ABI-007具有几个临床特点，包括输注速度快、不需要用药前治疗和高紫杉醇MTD。我们的结果为确定该药物的抗肿瘤活性的II期试验提供了支持。
PURPOSE ABI-007 is a novel Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. The absence of Cremophor EL may permit ABI-007 to be administered without the premedications used routinely for the prevention of hypersensitivity reactions. Furthermore, this novel formulation permits a higher paclitaxel concentration in solution and, thus, a decreased infusion volume and time. This Phase I study examines the toxicity profile, maximum tolerated dose (MTD), and pharmacokinetics of ABI-007. EXPERIMENTAL DESIGN ABI-007 was administered in the outpatient setting, as a 30-min infusion without premedications. Doses of ABI-007 ranged from 135 (level 0) to 375 mg/m2 (level 3). Sixteen patients participated in pharmacokinetic studies. RESULTS Nineteen patients were treated. No acute hypersensitivity reactions were observed during the infusion period. Hematological toxicity was mild and not cumulative. Dose-limiting toxicity, which occurred in 3 of 6 patients treated at level 3 (375 mg/m2), consisted of sensory neuropathy (3 patients), stomatitis (2 patients), and superficial keratopathy (2 patients). The MTD was thus determined to be 300 mg/m2 (level 2). Pharmacokinetic analyses revealed paclitaxel C(max) and area under the curve(inf) values to increase linearly over the ABI-007 dose range of 135-300 mg/m2. C(max) and area under the curve(inf) values for individual patients correlated well with toxicity. CONCLUSIONS ABI-007 offers several features of clinical interest, including rapid infusion rate, absence of requirement for premedication, and a high paclitaxel MTD. Our results provide support for Phase II trials to determine the antitumor activity of this drug.