Tissue distribution and brain penetration of niraparib in tumor bearing mouse models and its clinical relevance.
Authors: Gada Keyur , Sharma Geeta , Kmett Casey , Minthorn Elisabeth , Lugo David , Gehman Andrew , Fulci Giulia , Aziez Amine , Hazard Sebastien , Frenkl Tara L. , Roberts Simon 
Published: June 2021

e15066 Background: Cancer therapies that effectively cross the blood-brain barrier (BBB) to treat primary and metastatic brain tumors represent a critical unmet medical need. Brain metastasis are diagnosed in 10-40% of solid tumors and are associated with poor outcomes1. Preclinical data showed that niraparib has shown higher brain penetration as compared to other PARP inhibitors in an intact BBB setting2,3; however limited data is available to understand the penetration and residence of PARP inhibitors in a disrupted BBB setting. We conducted studies to assess the brain penetration of niraparib and olaparib in a disrupted BBB setting in an orthotopic animal tumor model. Additionally, we report tissue biodistribution of niraparib in a xenograft tumor mouse model. Methods: Brain penetration of niraparib and olaparib was assessed in GL261 orthotopic glioblastoma models. Niraparib and olaparib were dosed at 35 and 50 mg/kg once daily for 3-days, respectively. Brain tumor and contralateral normal brain region were excised following 3-day dosing. In a separate study niraparib tissue distribution in various organs was monitored in an ovarian (A2780) xenograft tumor mouse model. Several organs including tumors were excised following 5-day oral dosing of niraparib at 35mg/kg. Tissue samples were processed by homogenization followed by analysis using LC-MS/MS. Data were analyzed using non-compartmental analysis. Results: Mean drug concentrations at 2h post last dose in brain tumor region and normal contralateral brain region were 24µM and 2.15µM for niraparib compared with 0.7µM and 0.18µM for olaparib. Mean drug concentration at 24h post last dose in brain tumor region and normal contralateral region were 1.36µM and 0.53µM for niraparib compared with 0.17µM and 0.01µM for olaparib. In a A2780 xenograft tumor model tissue distribution study, niraparib demonstrated high levels of tissue penetration and retention in most perfused (lung, liver, kidney) and non-perfused tissues (tumor, ovary, pancreas). In most cases, tissues had at least 2-fold higher exposure than plasma at steady state following repeat oral dosing. Conclusions: Niraparib brain tumor tissue concentration was at least 25-fold greater than olaparib at 2h post dose. Data also suggests niraparib had better retention in brain tumor over olaparib with mean exposure as high as 1.4µM at 24h post dose (terminal phase) with just 3-days of dosing. These findings demonstrated that a favorable pharmacokinetic profile of niraparib was achieved in the disrupted BBB setting of the glioblastoma model. High penetration of niraparib in brain and other tissues along with a strong correlation with systemic exposures support the future investigation of niraparib in cancers with high incidence of brain metastasis. References: 1. Epidemiology, Biology, and Therapy; Chapter 1; 2015, Pages 3-29. 2. Oncotarget . 2018 Dec 14; 9(98): 37080–37096. 3. AACR 2019, Poster 3888.