Novartis Pharmaceuticals Corporation, Florham Park, New Jersey, USA.
Clin Pharmacol Ther. 2010 Feb;87(2):197-203. doi: 10.1038/clpt.2009.208. Epub 2009 Nov 18.
This article describes studies that investigated the pharmacokinetics of nilotinib, a highly specific, oral, second-generation BCR-ABL tyrosine kinase inhibitor. After a once- or twice-daily regimen at doses ranging from 50 to 1,200 mg/day in 119 patients with chronic myeloid leukemia (CML), the area under the serum concentration-time curve (AUC) and peak serum concentration (C(max)) of nilotinib were found to be nearly dose proportional up to a dose of 400 mg once daily. Solubility-limited absorption at higher doses was observed, but this was partially overcome by dividing the daily dose into two. For instance, the administration of 400 mg nilotinib twice daily resulted in a 35% increase in AUC as compared to a once-daily dose of 800 mg. Exploratory pharmacodynamic assessment showed a general trend of greater reduction in white blood cell (WBC) levels with increase in nilotinib concentrations. This finding was consistent with the observation of an 82% reduction in WBC levels in patients after a regimen of 400 mg nilotinib twice daily for 15 days. The type and quantity of food intake variably affected nilotinib absorption. When administered after a high-fat meal, the AUC of nilotinib increased by 50% in CML patients (n = 10) and by 82% in healthy volunteers (n = 44).
本文描述了对尼洛替尼（一种高度特异性、口服、第二代 BCR-ABL 酪氨酸激酶抑制剂）药代动力学的研究。在 119 例慢性髓性白血病（CML）患者中，每日一次或两次给予 50 至 1200mg 剂量后，发现尼洛替尼的血清浓度-时间曲线下面积（AUC）和血清峰浓度（C(max)）与剂量呈近比例关系，直至每日一次 400mg 剂量。在较高剂量时观察到溶解度限制吸收，但通过将每日剂量分为两次给药可部分克服。例如，与每日 800mg 一次剂量相比，每日两次给予 400mg 尼洛替尼可使 AUC 增加 35%。探索性药效学评估显示，随着尼洛替尼浓度的增加，白细胞（WBC）水平的降低呈普遍趋势。这一发现与每日两次 400mg 尼洛替尼方案治疗 15 天后，82%的患者 WBC 水平降低的观察结果一致。食物的类型和数量会影响尼洛替尼的吸收。在 CML 患者（n=10）和健康志愿者（n=44）中，尼洛替尼的 AUC 在高脂肪餐后分别增加了 50%和 82%。
