Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.
Cancer Chemother Pharmacol. 2014 Apr;73(4):673-83. doi: 10.1007/s00280-014-2374-3. Epub 2014 Jan 24.
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.
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).
There 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 μg/mL).
The 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.
一项评估舒尼替尼单药或联合拉帕替尼在日本实体瘤患者中的安全性、耐受性和药代动力学的 I 期研究。
在 A 部分（单药治疗），7 名患者最初接受 800mg/天的舒尼替尼治疗，这是推荐给非日本患者的剂量。然后，3 名患者在第 1 天接受 400mg/天的舒尼替尼，从第 2 天开始每天 800mg。另外 3 名患者接受 1000mg/天的舒尼替尼。在 B 部分（联合治疗），17 名患者接受舒尼替尼联合拉帕替尼（舒尼替尼/拉帕替尼），剂量为每日 1 次 400/1000mg（4 名患者）、800/1000mg（3 名患者）、400/1500mg（3 名患者），然后 600/1250mg（7 名患者）。
研究期间无剂量限制毒性。在 A 部分，大多数药物相关不良事件为 2 级或更低，包括中性粒细胞减少/中性粒细胞计数下降、血小板减少/血小板计数下降、腹泻、高血压、天门冬氨酸氨基转移酶升高和脂肪酶升高。在 B 部分，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，舒尼替尼多次给药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（20μg/ml）。
日本患者的舒尼替尼和拉帕替尼药代动力学特征与非日本患者报告的结果无明显差异。舒尼替尼和拉帕替尼之间没有一致的药物相互作用趋势。日本患者每日一次 800mg 和 1000mg 的舒尼替尼单药治疗以及研究中任何剂量的舒尼替尼联合拉帕替尼治疗均耐受良好。
