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Application of liquid chromatography-mass spectrometry to monitoring plasma cyclophosphamide levels in phase 1 trial cancer patients

Citation

Liu, JJ and Kestell, P and Findlay, M and Riley, G and Ackland, S and Simpson, A and Isaacs, R and McKeage, MJ, Application of liquid chromatography-mass spectrometry to monitoring plasma cyclophosphamide levels in phase 1 trial cancer patients, Clinical and Experimental Pharmacology and Physiology, 31, (10) pp. 677-682. ISSN 0305-1870 (2004) [Refereed Article]

Copyright Statement

Copyright 2004 John Wiley and Sons

DOI: doi:10.1111/j.1440-1681.2004.03065.x

Abstract

SUMMARY 1. A specific and efficient liquid chromatography–mass spectrometry (LC-MS) method was established for monitoring patient plasma cyclophosphamide levels in a phase I trial of an oral cyclophosphamide-based combination chemotherapy regimen. 2. An Agilent 1100 Series LC-MSD system (Agilent Technologies, Avondale, PA, USA), with a single quadrupole mass detector using a positive atmospheric pressure chemical ionization (APCI) interface and single ion monitoring at m/z 261, was used. Chromatography was performed using a LUNA C8 5  m 30  4.6 mm stainless steel column (Phenomenex, Torrance, CA, USA) and a mobile phase of aqueous acetonitrile pumped at a flow rate of 0.7 mL/min. High-throughput solid-phase sample extraction was performed using a Gilson ASPEC XL4 system (Gilson Medical, Middleton, WI, USA) controlled by prestored programs. 3. The standard curve for cyclophosphamide was linear over the concentration range 0.026–1.08  g/mL ( r 2 > 0.994). Intra- and interassay accuracy and precision were 97–107 and 3–10%, respectively. The limit of detection was determined to be 0.01  g/mL. Single ion monitoring at m/z 261 provided a high degree of specificity without interference from the matrix or other chemotherapy drugs. 4. Automated sample processing allowed the analysis of a large number of plasma samples from a clinical trial of repeated daily oral dosing of cyclophosphamide. One hour after dosing, cyclophosphamide was detected in 98 of 106 plasma specimens at concentrations ranging between 0.03 and 4.88  g/mL. Twenty-four hours after dosing, cyclophosphamide was detected in 72 of 77 plasma specimens at concentrations ranging between 0.06 and 3.13  g/mL. There were no time-dependent changes in cyclophosphamide concentration during the 43 day period of repeated daily oral dosing. There was no correlation between cyclophosphamide dose and plasma concentration, despite the wide range of doses given in the clinical trial (50–125 mg/m2). 5. We conclude that a solid-phase extraction LC-MS technique was validated for determining cyclophosphamide in human plasma. Interoccasion variability in the rate of oral absorption and in the clearance of systemically available drug may have contributed to the wide range of cyclophosphamide concentrations found at 1 and 24 h after tablet ingestion. Key words: cancer patients, cyclophosphamide, liquid chromatography–mass spectrometry, oral regimen, pharmacokinetics, phase I trial.

Item Details

Item Type:Refereed Article
Keywords:LC-MS, cyclophosphamide, cancer patient
Research Division:Medical and Health Sciences
Research Group:Pharmacology and Pharmaceutical Sciences
Research Field:Clinical Pharmacology and Therapeutics
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cancer and Related Disorders
Author:Liu, JJ (Dr Johnson Liu)
ID Code:89133
Year Published:2004
Web of Science® Times Cited:8
Deposited By:Pharmacy
Deposited On:2014-02-25
Last Modified:2014-08-01
Downloads:0

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