Phase 1 study of pazopanib alone or combined with lapatinib in Japanese patients with solid tumors
Phase 1 study of pazopanib alone or combined with lapatinib in Japanese patients with solid tumors
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DOI：
10.1007/s00280-014-2374-3
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发表时间：
2014-04-01
影响因子：
3
通讯作者：
Sasaki, Yasutsuna
中科院分区：
文献类型：
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作者：
Inada-Inoue, Megumi;Ando, Yuichi;Sasaki, Yasutsuna
Purpose甲1期研究帕唑帕尼单独或与拉帕替尼联合进行，以评估这些口服酪氨酸激酶抑制剂在日本患者的安全性，耐受性和药代动力学与solid tumors.Methods在A部分（单药治疗），7例患者最初接受帕唑帕尼800毫克/天，非日本患者的推荐剂量。然后，3名患者在第1天接受帕唑帕尼400 mg/天，然后从第2天开始接受800 mg/天。另外3名患者接受帕唑帕尼1，000 mg/天。在B部分（联合治疗）中，17例患者接受帕唑帕尼B+拉帕替尼（帕唑帕尼B/拉帕替尼）治疗，剂量分别为400/1，000 mg（4例患者），800/1，000 mg（3例患者），400/1，500 mg（3例患者），600/1，250 mg（7例患者）。在A部分，大多数药物相关不良事件为2级或更低级别，包括中性粒细胞减少/中性粒细胞计数降低、血小板减少/血小板计数降低、腹泻、高血压、天冬氨酸转氨酶升高和脂肪酶升高。在部分B中，还发生皮疹、食欲下降和血清促甲状腺激素升高。在所有剂量组中，多剂量帕唑帕尼后的血浆浓度超过了抑制血管内皮生长因子受体-2活性的目标谷浓度（20 μ g/mL）。结论日本患者中帕唑帕尼和拉帕替尼的药代动力学特征与非日本患者中报告的药代动力学特征无明显差异。帕唑帕尼和拉帕替尼之间的药代动力学药物相互作用没有一致的趋势。在日本患者中，帕唑帕尼单药治疗（800和1，000 mg，每日一次）和帕唑帕尼加拉帕替尼（任何研究剂量，每日一次）的耐受性良好。
Purpose A phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors.Methods In part A (monotherapy), 7 patients initially received pazopanib 800 mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400 mg/day on day 1 followed by 800 mg/day from day 2 onward. Three other patients received pazopanib 1,000 mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000 mg (4 patients), 800/1,000 mg (3 patients), 400/1,500 mg (3 patients), and then 600/1,250 mg (7 patients).Results T here was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20 mu g/mL).Conclusions T he pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000 mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.