Pfizer, Clinical Pharmacology, San Diego, California, USA.
Vertex, Clinical Pharmacology, Boston, Massachusetts, USA.
J Clin Pharmacol. 2022 Mar;62(3):376-384. doi: 10.1002/jcph.1971. Epub 2021 Nov 16.
Identification of a pharmacodynamic (PD) biomarker, which is predictive of the efficacy outcome, is of ultimate interest in drug development. The objectives of the current analyses are to develop the pharmacokinetic (PK)/PD model for biomarkers (thymidine kinase 1 [TK1] in serum and phosphor-retinoblastoma protein [pRb] and Ki67 in skin tissues) related to cyclin-dependent kinase (CDK) 4/6 inhibition by palbociclib and to explore the relationship of the biomarker response with the efficacy end point (progression-free survival). The data used for analysis consisted of extensive sampling of palbociclib PK and longitudinal rich sampling for the PD biomarkers TK1, pRb, and Ki67 in 26 patients. A 2-compartment model was used to describe the PK of palbociclib. A precursor-dependent indirect response PD model was developed to describe the pRb time course, whereas a similar PD model with an additional transit compartment to model the delayed effect on Ki67 and TK1 response was used to describe the Ki67 and TK1 time course. Palbociclib effect on biomarkers was modeled as a maximum inhibition model. A Cox proportional hazard model was used to assess the relationship of progression-free survival with the biomarker response. The PK/PD models adequately described the observed PK of palbociclib and the longitudinal change of pRb, Ki67, and TK1. Palbociclib exposure significantly correlated with the reduction of all 3 biomarkers, and the estimated concentration to achieve 50% inhibition of the synthesis rate values were 45.2, 42.4, 50.2 ng/mL, respectively, for pRb, Ki67, and TK1. The exploratory biomarker-response analyses showed that a longer PFS was associated with lower baseline TK1 and simulated minimum TK1. Such results may warrant further confirmation from future large-scale study. Clinical Trial Registration: NCT02499146.
鉴定药效（PD）生物标志物，预测疗效结果，是药物开发的最终目标。目前分析的目的是建立与 palbociclib 抑制细胞周期蛋白依赖性激酶（CDK）4/6 相关的生物标志物（血清中的胸苷激酶 1 [TK1]和皮肤组织中的磷酸化视网膜母细胞瘤蛋白 [pRb]和 Ki67）的药代动力学（PK）/PD 模型，并探索生物标志物反应与疗效终点（无进展生存期）的关系。用于分析的数据包括 palbociclib 的广泛 PK 采样和 26 名患者的 PD 生物标志物 TK1、pRb 和 Ki67 的纵向丰富采样。采用 2 室模型描述 palbociclib 的 PK。建立了一个依赖于前体的间接反应 PD 模型来描述 pRb 的时间过程，而使用类似的 PD 模型，增加一个转运室来模拟 Ki67 和 TK1 反应的延迟效应，来描述 Ki67 和 TK1 的时间过程。将 palbociclib 对生物标志物的作用建模为最大抑制模型。使用 Cox 比例风险模型评估无进展生存期与生物标志物反应的关系。PK/PD 模型充分描述了观察到的 palbociclib PK 和 pRb、Ki67 和 TK1 的纵向变化。palbociclib 暴露与所有 3 种生物标志物的降低显著相关，分别为 45.2、42.4 和 50.2ng/ml，估计抑制合成率的 50%的浓度值，用于 pRb、Ki67 和 TK1。探索性的生物标志物反应分析表明，更长的 PFS 与较低的基线 TK1 和模拟的最小 TK1 相关。这些结果可能需要进一步从未来的大规模研究中得到证实。临床试验注册：NCT02499146。
