Sun Kaiming, Mikule Keith, Wang Zebin, Poon Grace, Vaidyanathan Aparajitha, Smith Gillian, Zhang Zhi-Yi, Hanke Jeffrey, Ramaswamy Sridhar, Wang Jing
TESARO Inc, Waltham, MA, USA.
Division of Cellular Medicine, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, Dundee, UK.
Oncotarget. 2018 Dec 14;9(98):37080-37096. doi: 10.18632/oncotarget.26354.
Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both mutant (mut) and wildtype (wt) adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers who have demonstrated a complete or partial response to platinum-based chemotherapy. In patients without germline mutations (non-gmut), niraparib improved progression-free survival (PFS) by 5.4 months, whereas another PARP inhibitor (PARPi) olaparib supplied only 1.9 months of improvement in a similar patient population. Previous studies revealed higher cell membrane permeability and volume of distribution (V) as unique features of niraparib in comparison to other PARPi including olaparib. Here, we explore the potential correlation of these pharmacokinetic properties to preclinical antitumor effects in wt tumors. Our results show that at steady state, tumor exposure to niraparib is 3.3 times greater than plasma exposure in tumor xenograft mouse models. In comparison, the tumor exposure to olaparib is less than observed in plasma. In addition, niraparib crosses the blood-brain barrier and shows good sustainability in the brain, whereas sustained brain exposure to olaparib is not observed in the same models. Consistent with its favorable tumor and brain distribution, niraparib achieves more potent tumor growth inhibition than olaparib in wt models and an intracranial tumor model at maximum tolerated doses (MTD). These findings demonstrate favorable pharmacokinetic profiles and potent antitumor effects of niraparib in wt tumors, consistent with its broader clinical effect in patients with both mut and wt tumors.
尼拉帕利是一种口服生物利用度高的选择性聚（ADP - 核糖）聚合酶（PARP）-1/-2抑制剂，被批准用于对铂类化疗有完全或部分反应的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌的成年突变（mut）和野生型（wt）患者的维持治疗。在没有胚系突变（非gmut）的患者中，尼拉帕利将无进展生存期（PFS）提高了5.4个月，而另一种PARP抑制剂（PARPi）奥拉帕利在类似患者群体中仅提高了1.9个月的无进展生存期。先前的研究表明，与包括奥拉帕利在内的其他PARPi相比，尼拉帕利具有更高的细胞膜通透性和分布容积（V）。在此，我们探讨这些药代动力学特性与野生型肿瘤临床前抗肿瘤作用之间的潜在相关性。我们的结果表明，在稳态下，在肿瘤异种移植小鼠模型中，肿瘤对尼拉帕利的暴露量比血浆暴露量高3.3倍。相比之下，肿瘤对奥拉帕利的暴露量低于血浆中的观察值。此外，尼拉帕利可穿过血脑屏障并在脑中显示出良好的持续性，而在相同模型中未观察到奥拉帕利在脑中的持续暴露。与其有利的肿瘤和脑部分布一致，在野生型模型和颅内肿瘤模型中，尼拉帕利在最大耐受剂量（MTD）下比奥拉帕利实现了更强的肿瘤生长抑制。这些发现证明了尼拉帕利在野生型肿瘤中具有良好的药代动力学特征和强大的抗肿瘤作用，与其在突变型和野生型肿瘤患者中更广泛的临床效果一致。
