Pharmacokinetics, Dynamics, and Metabolism, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10777 Science Center Drive, San Diego, CA 92121, USA.
J Pharmacol Exp Ther. 2012 Mar;340(3):549-57. doi: 10.1124/jpet.111.188870. Epub 2011 Nov 30.
Crizotinib [Xalkori; PF02341066; (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine] is an orally available dual inhibitor of anaplastic lymphoma kinase (ALK) and hepatocyte growth factor receptor. The objectives of the present studies were to characterize: 1) the pharmacokinetic/pharmacodynamic relationship of crizotinib plasma concentrations to the inhibition of ALK phosphorylation in tumors, and 2) the relationship of ALK inhibition to antitumor efficacy in human tumor xenograft models. Crizotinib was orally administered to athymic nu/nu mice implanted with H3122 non-small-cell lung carcinomas or severe combined immunodeficient/beige mice implanted with Karpas299 anaplastic large-cell lymphomas. Plasma concentration-time courses of crizotinib were adequately described by a one-compartment pharmacokinetic model. A pharmacodynamic link model reasonably fit the time courses of ALK inhibition in both H3122 and Karpas299 models with EC(50) values of 233 and 666 ng/ml, respectively. A tumor growth inhibition model also reasonably fit the time course of individual tumor growth curves with EC(50) values of 255 and 875 ng/ml, respectively. Thus, the EC(50) for ALK inhibition approximately corresponded to the EC(50) for tumor growth inhibition in both xenograft models, suggesting that >50% ALK inhibition would be required for significant antitumor efficacy (>50%). Furthermore, based on the observed clinical pharmacokinetic data coupled with the pharmacodynamic parameters obtained from the present nonclinical xenograft mouse model, >70% ALK inhibition was projected in patients with non-small-cell lung cancer who were administered the clinically recommended dosage of crizotinib, twice-daily doses of 250 mg (500 mg/day). The result suggests that crizotinib could sufficiently inhibit ALK phosphorylation for significant antitumor efficacy in patients.
克唑替尼 [Xalkori；PF02341066；（R）-3-[1-（2,6-二氯-3-氟-苯基）-乙氧基]-5-（1-哌啶-4-基-1H-吡唑-4-基）-吡啶-2-基胺] 是一种可口服的间变性淋巴瘤激酶（ALK）和肝细胞生长因子受体双重抑制剂。本研究的目的是：1） 确定克唑替尼血浆浓度与肿瘤中 ALK 磷酸化抑制的药代动力学/药效学关系，2） 确定 ALK 抑制与人体肿瘤异种移植模型中抗肿瘤疗效的关系。将克唑替尼口服给予植入 H3122 非小细胞肺癌的无胸腺 nu/nu 小鼠或植入 Karpas299 间变大细胞淋巴瘤的严重联合免疫缺陷/ beige 小鼠。克唑替尼的药代动力学模型能够很好地描述其血浆浓度-时间曲线。药效学连接模型能够很好地拟合 H3122 和 Karpas299 模型中 ALK 抑制的时间曲线，其 EC50 值分别为 233 和 666ng/ml。肿瘤生长抑制模型也能够很好地拟合个体肿瘤生长曲线的时间曲线，其 EC50 值分别为 255 和 875ng/ml。因此，在这两种异种移植模型中，ALK 抑制的 EC50 值大约与肿瘤生长抑制的 EC50 值相对应，表明需要 >50%的 ALK 抑制才能达到显著的抗肿瘤疗效（>50%）。此外，根据观察到的临床药代动力学数据以及本非临床异种移植小鼠模型获得的药效学参数，接受推荐临床剂量克唑替尼（每日两次，每次 250mg，即 500mg/天）的非小细胞肺癌患者中，ALK 抑制率预计超过 70%。结果表明，克唑替尼可充分抑制 ALK 磷酸化，从而使患者获得显著的抗肿瘤疗效。
