Abstract 3581: Differentiation of niraparib and olaparib brain penetration in healthy rhesus macaque monkeys
Authors: Groseclose Mark Reid , Barry Jeremy , Pang Yongle , Deutsch Jennifer , Berry Shannon , McCormick Elaina , Lim David K. , Tran Hoang , Maguire Sean , Alsaid Hasan , Aziez Amine , Paul Elaine , Gada Keyur 
Published: April 2023

Purpose: There remains an unmet need to provide effective treatment therapy for patients with primary and metastatic brain tumors; lack of drug penetration across the blood brain barrier (BBB) is a key factor. Synthetic lethality is an attractive mechanism in treating brain tumors post radiotherapy. Here we investigate the brain penetration of niraparib and olaparib in healthy monkeys to understand the potential of each to cross the intact BBB.

Experimental Procedures: Four healthy male Rhesus macaque monkeys were dosed daily via oral gavage for five days with either niraparib (n=2; 6 mg/kg) or olaparib (n=2; 10 mg/kg). Pre-dose blood was collected daily and terminal blood, cerebrospinal fluid (CSF), and brain tissue was collected at necropsy. Coronal brain sections were analyzed by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) to quantitatively assess the tissue distribution of the dosed compounds. Blood, CSF, and bulk homogenate of brain tissue were analyzed by LC-MS bioanalysis.

Summary of Data: Greater brain penetration was observed for niraparib when compared to olaparib in healthy Rhesus macaque monkeys following five days oral administration. The unbound brain-to-plasma partition coefficient (Kp,uu,brain) was 15x higher for niraparib compared to olaparib. Quantitative MALDI IMS of coronal brain sections from monkeys administered niraparib showed consistent concentrations distributed throughout the brain parenchyma. Olaparib was not detected by MALDI IMS in any of the coronal brain sections collected from the monkeys administered olaparib. Similar plasma and CSF concentrations were observed between the monkey’s administered niraparib vs olaparib, highlighting the unique ability of niraparib to cross the intact BBB of monkeys and distribute throughout the brain.

Conclusions: Niraparib showed markedly higher brain penetration than olaparib in healthy Rhesus macaque monkeys demonstrating enhanced ability to cross intact BBB.

Summary of Quantification Results Displayed as Total Conc. with Adjusted Free Conc. in Parentheses Compound Animal LC-MS Pre-Dose Plasma Days 1-5 (ng/mL) LC-MS Pre-Dose Plasma Days 1-5 (ng/mL) LC-MS Terminal CSF (ng/mL) LC-MS Bulk Brain Homogenate (ng/g) MALDI IMS Brain Section Average (ng/g) Kp,uu Brain/Plasma Mean Kp, uu Brain/Plasma Niraparib Monkey 1 BLQ, 28 (10), 49 (18), 59 (22), 72 (26) 84 (31) 9 378 (14) 283 (10) 0.45 0.30 Niraparib Monkey 2 BLQ, 58 (21), 87 (32), 74 (27), 66 (24) 436 (160) 25 797 (29) 684 (25) 0.16 Olaparib Monkey 3 BLQ, 27 (8), 26 (8), 33 (10), 33 (10) 322 (99) 13 12 (2) BLQ 0.02 0.02 Olaparib Monkey 4 BLQ, 51 (16), 17 (5), 53 (16), 45 (14) 254 (78) 6 11 (2) BLQ 0.03

Citation Format: Mark Reid Groseclose, Jeremy Barry, Yongle Pang, Jennifer Deutsch, Shannon Berry, Elaina McCormick, David K. Lim, Hoang Tran, Sean Maguire, Hasan Alsaid, Amine Aziez, Elaine Paul, Keyur Gada. Differentiation of niraparib and olaparib brain penetration in healthy rhesus macaque monkeys. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3581.