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Clinical Trial
. 2018 Jan;81(1):39-46.
doi: 10.1007/s00280-017-3455-x. Epub 2017 Oct 17.

Determination of the Absolute Oral Bioavailability of Niraparib by Simultaneous Administration of a 14 C-microtracer and Therapeutic Dose in Cancer Patients

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Free PMC article
Clinical Trial

Determination of the Absolute Oral Bioavailability of Niraparib by Simultaneous Administration of a 14 C-microtracer and Therapeutic Dose in Cancer Patients

L van Andel et al. Cancer Chemother Pharmacol. .
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Abstract

Introduction: Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo.

Purpose: Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F po) of this novel compound, which is the aim of this study.

Methods: Six patients received an oral therapeutic dose of 300 mg niraparib, followed by a 15-min intravenous infusion of 100 µg 14C-niraparib with a radioactivity of approximately 100 nCi. The niraparib therapeutic dose was measured in plasma using a validated liquid chromatography-tandem mass spectrometry method, whereas the total 14C-radioactivity and 14C-niraparib plasma levels were measured by accelerator mass spectrometry and a validated high performance liquid chromatography assay with AMS.

Results: The F po of niraparib was determined to be 72.7% in humans.

Keywords: 14C-microtracer; AMS; Bioavailability; LC–MS/MS; Niraparib; Pharmacokinetics.

Conflict of interest statement

Funding

This study was sponsored by TESARO, Inc.

Conflict of interest

ZZ, LH, and VK are currently employees at TESARO, Inc. MS is employed at Xceleron, Inc. LA, HR, MMT, AG, JHMS and JHB are employed at the Netherlands Cancer Institute.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Molecular structure of 14C-niraparib tosylate salt. The asterisk denotes the position of the radioactive label in the IV formulation
Fig. 3
Fig. 3
Mean (± SD) log-linear plasma concentration–time profiles of 14C-radioactivity, 14C-niraparib, and unlabelled niraparib in patients with advanced cancer (n = 6). 14C-niraparib and total 14C-radioactivity levels are expressed as ng-equivalents/mL. The 14C-dose is administered 2 h after the oral dose. Three down error bars are not shown avoiding the inappropriate negative value. AMS accelerated mass spectrometry, LC–MS/MS liquid chromatography–tandem mass spectrometry

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