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

Kaiming Sun, Keith Mikule, Zebin Wang, Grace Poon, Aparajitha Vaidyanathan, Gillian Smith, Zhi Yi Zhang, Jeffrey Hanke, Sridhar Ramaswamy, Jing Wang

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)37080-37096
Number of pages17
JournalOncotarget
Volume9
Issue number98
DOIs
Publication statusPublished - 14 Dec 2018

Fingerprint

Pharmacokinetics
Neoplasms
Cell Membrane Permeability
niraparib
Poly(ADP-ribose) Polymerase Inhibitors
Maximum Tolerated Dose
Fallopian Tubes
Germ-Line Mutation
Brain
Platinum
Blood-Brain Barrier
Cell Size
Heterografts
Brain Neoplasms
Disease-Free Survival
olaparib
Drug Therapy
Growth
Population

Keywords

  • Brain exposure
  • BRCAwt tumor
  • Intracranial tumor
  • Niraparib
  • Tumor exposure

Cite this

Sun, Kaiming ; Mikule, Keith ; Wang, Zebin ; Poon, Grace ; Vaidyanathan, Aparajitha ; Smith, Gillian ; Zhang, Zhi Yi ; Hanke, Jeffrey ; Ramaswamy, Sridhar ; Wang, Jing. / A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models. In: Oncotarget. 2018 ; Vol. 9, No. 98. pp. 37080-37096.
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A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models. / Sun, Kaiming; Mikule, Keith; Wang, Zebin; Poon, Grace; Vaidyanathan, Aparajitha; Smith, Gillian; Zhang, Zhi Yi; Hanke, Jeffrey; Ramaswamy, Sridhar; Wang, Jing.

In: Oncotarget, Vol. 9, No. 98, 14.12.2018, p. 37080-37096.

Research output: Contribution to journalArticle

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AU - Mikule, Keith

AU - Wang, Zebin

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AU - Vaidyanathan, Aparajitha

AU - Smith, Gillian

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AU - Hanke, Jeffrey

AU - Ramaswamy, Sridhar

AU - Wang, Jing

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