Department of Pharmacokinetics, Pfizer Worldwide Research and Development, San Diego, California 92121, USA.
J Pharmacol Exp Ther. 2011 Sep;338(3):964-73. doi: 10.1124/jpet.111.181339. Epub 2011 Jun 16.
PF04942847 [2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide] was identified as an orally available, ATP-competitive, small-molecule inhibitor of heat shock protein 90 (HSP90). The objectives of the present study were: 1) to characterize the pharmacokinetic-pharmacodynamic relationship of the plasma concentrations of PF04942847 to the inhibition of HSP90-dependent protein kinase, AKT, as a biomarker and 2) to characterize the relationship of AKT degradation to tumor growth inhibition as a pharmacological response (antitumor efficacy). Athymic mice implanted with MDA-MB-231 human breast cancer cells were treated with PF04942847 once daily at doses selected to encompass ED(50) values. Plasma concentrations of PF04942847 were adequately described by a two-compartment pharmacokinetic model. A time delay (hysteresis) was observed between the plasma concentrations of PF04942847 and AKT degradation; therefore, a link model was used to account for the hysteresis. The model reasonably fit the time courses of AKT degradation with the estimated EC(50) of 18 ng/ml. For tumor growth inhibition, the signal transduction model reasonably fit the inhibition of individual tumor growth curves with the estimated EC(50) of 7.3 ng/ml. Thus, the EC(50) for AKT degradation approximately corresponded to the EC(50) to EC(80) for tumor growth inhibition, suggesting that 50% AKT degradation was required for significant antitumor efficacy (50-80%). The consistent relationship between AKT degradation and antitumor efficacy was also demonstrated by applying an integrated signal transduction model for linking AKT degradation to tumor growth inhibition. The present results will be helpful in determining the appropriate dosing regimen and guiding dose escalation to achieve efficacious systemic exposure in the clinic.
PF04942847 [2-氨基-4-{4-氯-2-[2-(4-氟-1H-吡唑-1-基)乙氧基]-6-甲基苯基}-N-(2,2-二氟丙基)-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-甲酰胺]被鉴定为一种可口服的、ATP 竞争性的小分子热休克蛋白 90（HSP90）抑制剂。本研究的目的是：1）描述 PF04942847 血浆浓度与 HSP90 依赖性蛋白激酶 AKT 抑制（作为生物标志物）之间的药代动力学-药效学关系，2）描述 AKT 降解与肿瘤生长抑制（作为药效学反应）的关系。荷瘤裸鼠（植入 MDA-MB-231 人乳腺癌细胞）每天接受一次 PF04942847 治疗，剂量选择涵盖 ED（50）值。PF04942847 的血浆浓度用双室药代动力学模型充分描述。PF04942847 血浆浓度与 AKT 降解之间存在时间滞后（滞后）；因此，使用链接模型来解释滞后。该模型合理地拟合了 AKT 降解的时间过程，其 EC（50）估计值为 18ng/ml。对于肿瘤生长抑制，信号转导模型合理地拟合了单个肿瘤生长曲线的抑制，其 EC（50）估计值为 7.3ng/ml。因此，AKT 降解的 EC（50）大约与肿瘤生长抑制的 EC（50）至 EC（80）相对应，这表明 50%AKT 降解对于显著的抗肿瘤疗效（50-80%）是必需的。通过应用将 AKT 降解与肿瘤生长抑制联系起来的综合信号转导模型，也证明了 AKT 降解与抗肿瘤疗效之间的一致关系。这些结果将有助于确定适当的给药方案并指导剂量递增，以在临床中实现有效的全身暴露。
