Abstract 3026: Evaluation of brain pharmacokinetics (PK) and tumor growth inhibition of PARP inhibitors in mouse xenograft models using semi-mechanistic PK/pharmacodynamic (PD) modeling
Authors: Liao Michelle , Jin Feng , Nguyen Minh , Robillard Liliane , Simmons Andrew D. , Harding Thomas C. , Xiao Jim J. 
Published: September 2020

OBJECTIVE: The PARP inhibitors rucaparib, niraparib, olaparib, and veliparib have shown remarkable antitumor activity against various cancer types. We evaluated the brain penetration of PARP inhibitors in mice and the anti-tumor effects of selected PARP inhibitors in orthotopic and intracranial BRCA1-mutant triple-negative breast cancer (TNBC) MDA-MB-436 mouse models. PK/PD models were used to characterize the systemic/brain PK and tumor growth inhibition.

METHODS: In non-tumor-bearing NOD-SCID female mice, plasma concentrations were determined at selected time points following an oral dose of 2, 5, 15, 50, or 150 mg rucaparib. The antitumor efficacy of rucaparib (2, 5, 15, 50, or 150 mg BID for 28 days) was evaluated in the MDA-MB-436 orthotopic model. In addition, a single dose of rucaparib (150 mg), niraparib (50 mg), olaparib (150 mg), or veliparib (150 mg) was given to male CD-1 mice; plasma, brain, and cerebrospinal fluid (CSF) concentrations of these compounds were determined at various time points. Intracranial efficacy was evaluated in luciferase-expressing MDA-MB-436 tumors following treatment of rucaparib (150 mg BID) or niraparib (50 mg QD) for 57 days. Tumor burden was evaluated using bioluminescence measurements. Semi-mechanistic PK and tumor growth inhibition models were developed to evaluate systemic, brain, and CSF concentration-time profiles for all 4 PARP inhibitors, and to evaluate tumor inhibition for rucaparib and niraparib using NONMEM software.

RESULTS: All of the PARP inhibitors showed limited brain penetration in mice with an intact blood-brain barrier. However, rucaparib and niraparib demonstrated antitumor efficacy in a BRCA1-mutant, intracranial, TNBC mouse model. Brain and CSF concentrations were modeled as separate physiologically relevant compartments with PARP inhibitors being able to distribute to both brain and CSF compartments from the systemic compartment following oral administration. The model characterized plasma, brain, and CSF drug concentrations simultaneously. A modified Simeoni model with a 1st-order tumor growth rate adequately described the dose-dependent tumor inhibition at different doses of rucaparib in the orthotopic tumor model. The effects of brain tumor inhibition by rucaparib and niraparib were sufficiently described by a simpler model with a 1st-order tumor growth rate and a 2nd-order tumor inhibition rate that was proportional to brain drug concentrations.

CONCLUSIONS: Systemic and brain concentrations, as well as orthotopic and intracranial tumor inhibition data, following oral administration in mice, were adequately described using semi-mechanistic models. Further studies are warranted to understand the intracranial distribution and antitumor activity of PARP inhibitors.

Citation Format: Michelle Liao, Feng Jin, Minh Nguyen, Liliane Robillard, Andrew D. Simmons, Thomas C. Harding, Jim J. Xiao. Evaluation of brain pharmacokinetics (PK) and tumor growth inhibition of PARP inhibitors in mouse xenograft models using semi-mechanistic PK/pharmacodynamic (PD) modeling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3026.