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A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models.

ABSTRACT: Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both BRCA mutant (mut) and BRCA 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 BRCA mutations (non-gBRCAmut), 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 (VD) 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 BRCAwt 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 BRCAwt models and an intracranial tumor model at maximum tolerated doses (MTD). These findings demonstrate favorable pharmacokinetic profiles and potent antitumor effects of niraparib in BRCAwt tumors, consistent with its broader clinical effect in patients with both BRCAmut and BRCAwt tumors.

SUBMITTER: Sun K

PROVIDER: S-EPMC6324689 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models.

Sun Kaiming K Mikule Keith K Wang Zebin Z Poon Grace G Vaidyanathan Aparajitha A Smith Gillian G Zhang Zhi-Yi ZY Hanke Jeffrey J Ramaswamy Sridhar S Wang Jing J

Oncotarget 20181214 98

Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both BRCA mutant (mut) and BRCA 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 BRCA mutations (non-gBRCAmut), niraparib improved progression-free survival ( ...[more]

PMID: 30647846

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Project description:Poly (ADP-ribose) polymerases (PARPs) are an important family of nucleoproteins highly implicated in DNA damage repair. Among the PARP families, the most studied are PARP1, PARP2 and PARP 3. PARP1 is found to be the most abundant nuclear enzyme under the PARP series. These enzymes are primarily involved in base excision repair as one of the major single strand break (SSB) repair mechanisms. Being double stranded, DNA engages itself in reparation of a sub-lethal SSB with the aid of PARP. Moreover, by having a sister chromatid, DNA can also repair double strand breaks with either error-free homologous recombination or error-prone non-homologous end-joining. For effective homologous recombination repair, DNA requires functional heterozygous breast cancer genes (BRCA) which encode BRCA1/2. Currently, the development of PARP inhibitors has been one of the promising breakthroughs for cancer chemotherapy. In March 2017, the United States Food and Drug Administration (FDA) approved niraparib for maintenance therapy of recurrent gynecologic cancers (epithelial ovarian, primary peritoneal and fallopian tube carcinomas) which are sensitive to previous platinum based chemotherapy irrespective of BRCA mutation and homologous recombination deficiency status. It is the third drug in this class to receive FDA approval, following olaparib and rucaparib and is the first global approval for maintenance therapy of the aforementioned cancers. Niraparib preferentially blocks both PARP1 and PARP2 enzymes. The daily tolerated dose of niraparib is 300 mg, above which dose limiting grade 3 and 4 toxicities were observed. In combination with humanized antibody, pembrolizumab, it is also under investigation for those patients who have triple negative breast cancer. By and large, there are several clinical trials that are underway investigating clinical efficacy and safety, as well as other pharmacokinetic and pharmacodynamic profiles of this drug for various malignancies.

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A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models.

Publications

A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models.

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