Phase I and pharmacokinetic study of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, by twice daily oral administration between meals in patients with advanced solid tumors.
Phase I and pharmacokinetic study of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, by twice daily oral administration between meals in patients with advanced solid tumors.
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DOI：
10.1007/s00280-010-1404-z
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发表时间：
2011-05
影响因子：
3
通讯作者：
Tamura, Tomohide
中科院分区：
文献类型：
--
作者：
Ueda, Yutaka;Shimoyama, Tatsu;Murakami, Haruyasu;Yamamoto, Noboru;Yamada, Yasuhide;Arioka, Hitoshi;Tamura, Tomohide
对新型多受体酪氨酸激酶抑制剂 TSU-68 进行了单药剂量递增的 I 期和药代动力学研究，以确定日本晚期实体瘤患者的安全性、最大耐受剂量，并确定 II 期研究的推荐剂量。研究设计是针对三名患者的队列的剂量递增方法。 TSU-68 每日两次（bid）在两餐之间口服给药，不间断；剂量递增的估计是基于每个剂量水平给药 4 周内的毒性。十五名患者被纳入该研究。研究的剂量水平为 200、400、800 和 1,200 mg/m2 bid。 800 mg/m2 bid 时，各 1 名患者出现 3 级心律失常和贫血/血小板减少症。三名患者以 400 和 800 mg/m2 bid 的剂量连续口服给药 4 周。在 1,200 mg/m2 bid 时，2 名患者分别因难以忍受的疲劳和腹痛而停止治疗超过 4 周。尚未观察到严重的药物相关毒性。 1-2 级毒性包括尿液/粪便变色、腹泻、疲劳、厌食、腹痛/胸痛和水肿。 1 例 NSCLC 患者观察到肿瘤缩小。在药代动力学中，在任何剂量水平，TSU-68在第8天和第29天重复给药后的Cmax和AUC0–t比第1天首次给药后低约2倍；这些参数在第8天和第28天之间相似。此外，在四个剂量水平（包括较高剂量水平）中，重复施用的TSU-68的血浆暴露没有观察到明显的剂量依赖性增加。本给药方案中持续治疗的耐受剂量被认为是 800 mg/m2 或更少 bid。
A single-agent dose-escalating phase I and pharmacokinetic study on TSU-68, a novel multiple receptor tyrosine kinase inhibitor, was performed to determine the safety profile, maximum-tolerated dose for Japanese patients with advanced solid tumors and to define the recommended dose of phase II studies. Study design was a dose escalation method on a three-patient cohort. TSU-68 was given orally twice daily (bid) between meals without interruption; the estimation of dose escalation was based on the toxicity within 4 week administration at each dose level. Fifteen patients were enrolled into the study. Dose levels studied were 200, 400, 800, and 1,200 mg/m2 bid. Grade 3 arrhythmia and anemia/thrombocytopenia were observed in 1 patient each at 800 mg/m2 bid. Three patients discontinued continuous oral administration for 4 weeks at 400 and 800 mg/m2 bid. At 1,200 mg/m2 bid, 2 patients discontinued the treatment over 4 weeks for intolerable fatigue and abdominal pain, respectively. No serious drug-related toxicities have been observed. Grade 1–2 toxicity included urinary/feces discoloration, diarrhea, fatigue, anorexia, abdominal/chest pain, and edema. Tumor shrinkage was observed in 1 patient of NSCLC. In the pharmacokinetics, at any dose levels, Cmax and AUC0–t after repeated administration of TSU-68 on days 8 and 29 were ~2-fold lower that those after the first administration on day 1; these parameters are similar between days 8 and 28. In addition, no obvious dose-dependent increase in plasma exposure to TSU-68 repeatedly administered was observed over the four dose levels, including the higher dose levels. The tolerable dose in this administration schedule for continuing treatment is thought to be 800 mg/m2 or less bid.
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影响因子：
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