A rapid and sensitive method for determination of veliparib (ABT-888), in human plasma, bone marrow cells and supernatant by using LC/MS/MS

Abstract

A rapid and sensitive method was developed and validated using a liquid chromatographic method with tandem mass spectrometry detection (LC/MS/MS) for determination of veliparib (ABT-888) in plasma, bone marrow supernatant, and bone marrow cells. Sample preparation involved a single protein precipitation step by the addition of the sample with acetonitrile. Separation of veliparib and the internal standard, A620223.69, was achieved on a Atlantis™ dC18 column (100 × 2.1 mm, 3 μm) column using a mobile phase consisting of acetonitrile-ammonium acetate (2 mM) containing formic acid (0.1 %, v/v) using isocratic flow at 0.2 mL/min for 3 minutes. The analyte and internal standard were monitored by tandem-mass spectrometry with electrospray positive ionization. Linear calibration curves were generated over the range of 5 to 1000 nM. The values for both within day and between day precision and accuracy were well within the generally accepted criteria for analytical methods. This method was subsequently used to measure concentrations of veliparib in cancer patients receiving an oral daily dose of 10 mg with demonstration of drug accumulation in the marrow compartment and in the target leukemia bone marrow cells.

A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia

“…Plasma samples obtained on day 1 of veliparib and on day 4 after the first dose of veliparib in combination with topotecan + carboplatin were assayed for veliparib using the validated LC/MS/MS method (33). PK variables were calculated by standard noncompartmental methods using Phoenix ® WinNonlin ® version 6.3 (Pharsight A Certara™ Company, Cary, NC) as previously described (34).…”

Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth

“…To this end, plasma was combined with 1.2N perchloric acid then vortexed and centrifuged. Bone marrow supernatant was treated similarly (24,25). All samples were further diluted with HPLC water to reduce matrix interferences.…”

Population pharmacokinetics and site of action exposures of veliparib with topotecan plus carboplatin in patients with haematological malignancies

“…These samples were collected 4–7 h post‐dose on days 1 and 4. The veliparib concentrations in plasma, bone marrow cells and supernatant were quantified using liquid chromatography‐tandem mass spectrometry (LC/MS/MS) bioanalytical method .…”