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Chromatography 2014, 1(2), 82-95; doi:10.3390/chromatography1020082
Article

A Sensitive and Robust Ultra HPLC Assay with Tandem Mass Spectrometric Detection for the Quantitation of the PARP Inhibitor Olaparib (AZD2281) in Human Plasma for Pharmacokinetic Application

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1 Clinical Pharmacology Program, Office of the Clinical Director, National Cancer Institute, Bethesda, MD 20892, USA 2 AstraZeneca Pharmaceuticals, Alderley Park Macclesfield, Cheshire SK10 4TG, UK 3 Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA
* Author to whom correspondence should be addressed.
Received: 26 March 2014 / Revised: 12 May 2014 / Accepted: 12 June 2014 / Published: 19 June 2014
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Abstract

Olaparib (AZD2281) is an orally active PARP-1 inhibitor, primarily effective against cancers with BRCA1/2 mutations. It is currently in Phase III development and has previously been investigated in numerous clinical trials, both as a single agent and in combination with chemotherapy. Despite this widespread testing, there is only one published method that provides assay details and stability studies for olaparib alone. A more sensitive uHPLC-MS/MS method for the quantification of olaparib in human plasma was developed, increasing the range of quantification at both ends (0.5–50,000 ng/mL) compared to previously published methods (10–5,000 ng/mL). The wider range encompasses CMAX levels produced by typical olaparib doses and permits better pharmacokinetic modeling of olaparib elimination. This assay also utilizes a shorter analytical runtime, allowing for more rapid quantification and reduced use of reagents. A liquid-liquid extraction was followed by chromatographic separation on a Waters UPLC® BEH C18 column (2.1 × 50 mm, 1.7 µm) and mass spectrometric detection. The mass transitions m/z 435.4→281.1 and m/z 443.2→281.1 were used for olaparib and the internal standard [2H8]-olaparib, respectively. The assay proved to be accurate (<9% deviation) and precise (CV < 11%). Stability studies showed that olaparib is stable at room temperature for 24 h. in whole blood, at 4 °C for 24 h post-extraction, at −80 °C in plasma for at least 19 months, and through three freeze-thaw cycles. This method proved to be robust for measuring olaparib levels in clinical samples from a Phase I trial.
Keywords: poly(ADP-ribose) polymerase inhibitor; olaparib; ultra-high performance liquid chromatography; tandem mass spectrometry; pharmacokinetics poly(ADP-ribose) polymerase inhibitor; olaparib; ultra-high performance liquid chromatography; tandem mass spectrometry; pharmacokinetics
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Roth, J.; Peer, C.J.; Mannargudi, B.; Swaisland, H.; Lee, J.-M.; Kohn, E.C.; Figg, W.D. A Sensitive and Robust Ultra HPLC Assay with Tandem Mass Spectrometric Detection for the Quantitation of the PARP Inhibitor Olaparib (AZD2281) in Human Plasma for Pharmacokinetic Application. Chromatography 2014, 1, 82-95.

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