e13552 Background: Within the past several years multiple PARP inhibitors have been entered into clinical trials, in a variety of tumors types with defective homology-directed DNA repair. An understanding of the degree of PARP inhibition produced by these inhibitors is critical in understanding potential drug effectiveness. Pharmacodynamic (PD) data, specifically PARP inhibition in peripheral blood lymphocytes (PBLs), have been reported for PF-01367338, olaparib and MK-4827, which provides an opportunity to compare the PD effect of these compounds. The objective of this study was to compare PARP inhibition following PF-01367338 daily IV dosing to those achieved by olaparib and MK-4821. METHODS PARP inhibition (percent change of PAR from baseline) data for PF-01367338 were obtained from the Phase 1 study of PF-01367338 given daily in combination with temozolomide for 5 days. Olaparib and MK-4821 data were obtained from the exposure or dose/response curves reported in the literature. Comparisons were made using PD data from PF-01367338 matched to those reported for each compound, including (a) the average PARP inhibition over the dosing interval for comparison with olaparib, and (b) the PARP inhibition at the end of dosing interval for comparison with MK-4827. Maximum inhibition (Emax), the endpoint used for the comparison of inhibitory performance, was either determined by PK/PD modelling (PF-01367338 and Olaparib) or obtained from the average inhibition at the dose levels where PARP inhibition in PBLs reached plateau (MK-4827). The corresponding range for Emax was obtained from observed data for the relevant comparison at the dose or exposure level(s) where Emax was achieved. RESULTS Comparison of Emax achieved (see table). Values for Olaparib and MK-4827 were read off the published figures thus approximate. CONCLUSIONS PF-01367338 provides an average increase of 22-27% in PARP inhibition with less inter-patient variability compared to olaparib or MK-4827. Future studies are planned to determine if this finding translates into an increase in anti-tumor response. [Table: see text].

中文翻译：

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PF-01367338、olaparib 和 MK-4827 的 PARP 酶抑制比较。

e13552 背景：在过去几年中，多种 PARP 抑制剂已进入临床试验，用于具有缺陷的同源定向 DNA 修复的多种肿瘤类型。了解这些抑制剂产生的 PARP 抑制程度对于了解潜在的药物有效性至关重要。PF-01367338、olaparib 和 MK-4827 的药效学 (PD) 数据，特别是外周血淋巴细胞 (PBLs) 中的 PARP 抑制作用，为比较这些化合物的 PD 效果提供了机会。本研究的目的是将 PF-01367338 每日静脉给药后的 PARP 抑制与奥拉帕尼和 MK-4821 实现的抑制进行比较。方法 PF-01367338 的 PARP 抑制（PAR 相对于基线的百分比变化）数据来自 PF-01367338 每天与替莫唑胺联合给药 5 天的 1 期研究。Olaparib 和 MK-4821 数据来自文献中报道的暴露或剂量/反应曲线。使用来自 PF-01367338 的 PD 数据与每种化合物报告的数据进行比较，包括 (a) 给药间隔内的平均 PARP 抑制以与奥拉帕尼进行比较，以及 (b) 给药间隔结束时的 PARP 抑制以进行比较与 MK-4827。最大抑制 (Emax)，用于比较抑制性能的终点，要么通过 PK/PD 模型（PF-01367338 和 Olaparib）确定，要么从 PBL 中 PARP 抑制达到平台期（MK -4827）。Emax 的相应范围是从在达到 Emax 的剂量或暴露水平下进行相关比较的观察数据中获得的。结果 达到的 Emax 比较（见表）。Olaparib 和 MK-4827 的值是从公布的数字中读出的，因此是近似值。结论与奥拉帕尼或 MK-4827 相比，PF-01367338 的 PARP 抑制平均增加 22-27%，患者间变异性更小。未来的研究计划确定这一发现是否会转化为抗肿瘤反应的增加。[表：见正文]。结论 与奥拉帕尼或 MK-4827 相比，PF-01367338 的 PARP 抑制平均增加 22-27%，患者间变异性更小。未来的研究计划确定这一发现是否会转化为抗肿瘤反应的增加。[表：见正文]。结论与奥拉帕尼或 MK-4827 相比，PF-01367338 的 PARP 抑制平均增加 22-27%，患者间变异性更小。未来的研究计划确定这一发现是否会转化为抗肿瘤反应的增加。[表：见正文]。