Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity
Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity
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DOI：
10.1158/1535-7163.mct-07-0193
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发表时间：
2007-07-01
影响因子：
5.7
通讯作者：
Cheung, Mui
中科院分区：
文献类型：
--
作者：
Kumar, Rakesh;Knick, Victoria B.;Cheung, Mui
随着靶向治疗的发展，尤其是对小分子抑制剂的靶向治疗，了解体内观察到的疗效是否与体内预期/预期靶点的调节有关变得重要。我们已经开发出三种血管内皮生长因子受体(VEGFR)、血小板衍生生长因子受体和c-Kit酪氨酸激酶的小分子抑制剂pazopanib(GW786034)，它可以选择性地抑制VEGF诱导的内皮细胞增殖。具有良好的经口暴露，抑制小鼠血管生成和肿瘤生长。由于团注给药导致C-max和C-槽的巨大差异，我们研究了持续输注VEGFR抑制剂对肿瘤生长和血管生成的影响。GW771806与GW786034具有相似的酶和细胞特性，由于输液研究对溶解度的要求更高，因此被用于这些研究。比较两种不同给药途径的药代动力学(丸剂P.O.剂量和持续输注)，我们发现VEGFR抑制剂的抗肿瘤和抗血管生成活性依赖于超过阈值的化合物的稳态浓度。这些作用所需的稳态浓度与抑制血管内皮生长因子诱导的小鼠肺内VEGFR2磷酸化所需的浓度一致。此外，根据临床前活性确定的帕佐帕尼的稳态浓度与I期临床试验中的药效学效应和抗肿瘤活性有很强的相关性。
With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C-max and C-trough, we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.