Application of liquid chromatography-mass spectrometry to monitoring plasma cyclophosphamide levels in phase I trial cancer patients
2004
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.
Keywords:
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