The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor
The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor
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DOI：
10.1007/s10637-007-9083-2
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发表时间：
2008-02-01
影响因子：
3.4
通讯作者：
Hanauske, Axel-Rainer
中科院分区：
文献类型：
--
作者：
Holen, Kyle;Saltz, Leonard B.;Hanauske, Axel-Rainer
背景 FK866 是一种有效的 NAD 合成抑制剂。这项首次人体研究的目的是确定 96 小时连续输注方案的最大耐受剂量、毒性特征和药代动力学。材料和方法 24 名患有标准疗法难治性晚期实体瘤的患者接受递增剂量的 FK866 治疗，每 28 天连续输注 96 小时。收集系列血浆样本以表征 FK866 的药代动力学。进一步收集血样用于测量血浆 VEGF 水平。结果 12 名女性和 12 名男性，中位年龄 61 岁（范围 34-78），中位 KPS 为 80%，接受 FK866 输注 4 天，剂量水平为 0.018 mg/m(2)/h (n=3)、0.036 mg/m(2)/h (n=3)、0.072 mg/m(2)/h (n=3)、0.108 mg/m(2)/h (n=4)、0.126 mg/m(2)/h (n=6) 和 0.144 mg/m(2)/h (n=5)。血小板减少症是剂量限制性毒性，在最高剂量水平的两名患者和一名推荐 II 期剂量 0.126 mg/m2/h 的患者中观察到，除了轻度淋巴细胞减少和贫血外，没有发现其他血液学毒性。有轻度疲劳和3级恶心；后者是通过止吐药控制的，不是 DLT。 C-ss（72 小时和 96 小时血浆浓度的平均值）随着剂量的增加而增加。研究药物没有显着影响 VEGF 的血浆浓度。尽管 4 名患者病情稳定（治疗 3 个月或更长时间），但没有出现客观缓解。结论 推荐的 II 期剂量为 0.126 mg/m(2)/h，每 28 天连续输注 96 小时。 FK866 的剂量限制性毒性是血小板减少症。药代动力学数据表明血浆 C-ss 的增加与 FK866 的增加有关。
Background FK866 is a potent inhibitor or NAD synthesis. This first-in-human study was performed to determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics on a 96-h continuous infusion schedule. Materials and methods Twenty four patients with advanced solid tumor malignancies refractory to standard therapies were treated with escalating doses of FK866 as a continuous, 96-h infusion given every 28 days. Serial plasma samples were collected to characterize the pharmacokinetics of FK866. Further blood samples were collected for the measurement of plasma VEGF levels. Results There were 12 women and 12 men with a median age of 61 (range 34-78) and a median KPS of 80%, received a 4-day of infusion of FK866 at dose levels of 0.018 mg/m(2)/h (n=3), 0.036 mg/m(2)/h (n=3), 0.072 mg/m(2)/h (n=3), 0.108 mg/m(2)/h (n=4), 0.126 mg/m(2)/h (n=6), and 0.144 mg/m(2)/h (n=5). Thrombocytopenia was the dose limiting toxicity, observed in two patients at the highest dose level and one patient at the recommended phase II dose of 0.126 mg/m2/h No other hematologic toxicities were noted other than mild lymphopenia and anemia. There was mild fatigue and grade 3 nausea; the latter was controlled with antiemetics and was not a DLT. C-ss (the mean of the 72 and 96 h plasma concentrations) increased in relation to the dose escalation. The study drug did not significantly affect plasma concentrations of VEGF. There were no objective responses, although four patients had stable disease (on treatment for 3 months or greater). Conclusions The recommended phase II dose is 0.126 mg/m(2)/h given as a continuous 96-h infusion every 28 days. The dose limiting toxicity of FK866 is thrombocytopenia. Pharmacokinetic data suggest an increase in the plasma C-ss in relation to the escalation of FK866.