A Simple and Sensitive High-Performance Liquid Chromatographic Method for Quantification of PXD101, a Histone Deacetylase Inhibitor in Human Plasma

Abstract

PXD101, a new histone deacetylase inhibitor, is currently undergoing phase I/II clinical trials as an anticancer drug. This study describes a simple and sensitive high-performance liquid chromatography ultraviolet method developed for the quantification of PXD101 in human plasma samples to support such trials. Following solid phase extraction at room temperature, the analytes were separated on a 5 mum C18 150 x 2.1 mm column using gradient elution (mobile phase of acetonitrile and 25 mM NaH2PO4, pH 2.8) at a flow rate of 0.5 mL/min and ultraviolet detection at 268 nm. Oxamflatin was used as an internal standard. PXD101 and the internal standard were eluted at about 7.9 min and 13.6 min, respectively. The lower limit of quantification of PXD101 in plasma was 10 ng/mL. The calibration curves for concentrations in the range of 10 to 2,000 ng/mL gave excellent linearity (r = 0.999). The coefficients of variation for intraday and interday assays were all less than 10%. The accuracy of all concentration determinations ranged from 98.0% to 102.0%. There were no problems with PXD101 stability following freeze-thawing, short-term exposure to room temperature, postextraction stability up to 24 hours, and sample storage at -70 degrees C for 3 months. The reported method, with dilution integrity of up to 50 fold, has the requisite sensitivity and is suitable for pharmacokinetic studies of PXD101.

A sensitive and specific liquid chromatography–tandem mass spectrometric method for determination of belinostat in plasma from liver cancer patients

“…Initially, we developed and validated a HPLC-UV assay with the lower limit of quantification (LLOQ) of 10 ng/mL for the determination of belinostat in human plasma [8]. However, concentrations in the plasma samples taken at 24 h after the start of infusion are usually too low to be quantified by the current HPLC-UV assay due to fast disposition of belinostat in the human body.…”

Review of bioanalytical assays for the quantitation of various HDAC inhibitors such as vorinostat, belinostat, panobinostat, romidepsin and chidamine

“…The reviewed case studies of representative HDAC inhibitors in this report have adequately demonstrated the key bioanalytical challenges for the quantitation of various HDAC inhibitors. It is of interest to note that only a few HPLC methods ( n = 3) are reported for the quantification of various HDAC inhibitors (Mullangi et al ., ; Zhang et al ; Chassaing et al ., ) in biological samples. One of the methods used SPE and the other two methods used LLE.…”

“…Zhang et al . () quantified PXD101 (belinostat) in human plasma using SPE and separation was done using a reverse‐phase column connected to a UV detector. Mullangi et al .…”

Validation of an LC–MS/MS method for simultaneous detection of four HDAC inhibitors – belinostat, panobinostat, rocilinostat and vorinostat in mouse plasma and its application to a mouse pharmacokinetic study

“…A detailed survey of literature revealed that several HPLC and LC–MS/MS methods have been published for the determination of belinostat (BST), panobinostat (PST), rocilinostat (RST) and vorinostat (VST) individually [for BST – Kiesel et al (); Wang et al (); Zhang et al (); for PST – Estella‐Hermoso de Mendoza et al (); for RST – Gupta et al (); and for VST – Mullangi et al (); Liu et al (); Mohamed et al (); Wu, Chen, Wen, Zhang, and Lin (); Patel, Guichard, and Jodrell (); Parise, Holleran, Beumer, Ramalingam, and Egorin (); Du, Musson, and Wang ()] or along with other drug(s) [for VST with other drugs ‐ Yeo et al ()] in various biological matrices. We recently published an extensive review on bioanalytical methods for quantitation of HDACIs in various biological matrices using HPLC and LC–MS/MS (Suresh, Devaraj, Srinivas, & Mullangi, ).…”