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

Helen Swaisland¹  Baskar Mannargudi²  Cody J. Peer²  William D. Figg²  Jeffrey Roth²  Jung-Min Lee³  Elise C. Kohn³ 

[1] AstraZeneca Pharmaceuticals, Alderley Park Macclesfield, Cheshire SK10 4TG, UK;Clinical Pharmacology Program, Office of the Clinical Director, National Cancer Institute, Bethesda, MD 20892, USA;Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA;

关键词: poly(ADP-ribose) polymerase inhibitor;    olaparib;    ultra-high performance liquid chromatography;    tandem mass spectrometry;    pharmacokinetics;   

DOI  :  10.3390/chromatography1020082

来源: DOAJ

【 摘 要 】

Olaparib (AZD2281) is an orally active PARP-1 inhibitor, primarily effective against cancers with BRCA1/2 mutations. It is currently in Phase III development andhas 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 for24 h post-extraction, at −80 °C in plasma for at least 19 months, and through threefreeze-thaw cycles. This method proved to be robust for measuring olaparib levels in clinical samples from a Phase I trial.

【 授权许可】

Unknown