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Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates.

Abstract：

PURPOSE:Pemetrexed, a multi-targeted antifolate that disrupts synthesis of both purines and pyrimidines, is approved for use in malignant pleural mesothelioma and non-small cell lung cancer. Pemetrexed is currently being evaluated for anti-tumor activity in a variety of solid and central nervous system tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of pemetrexed in a non-human primate model that is highly predictive of human CSF penetration. METHODS:Pemetrexed, 20 mg/kg (400 mg/m2), was administered intravenously to four non-human primates. Serial blood samples were obtained from all animals and serial CSF samples were obtained from three animals. Plasma and CSF concentrations of pemetrexed were measured using LC/MS/MS and the resulting concentration versus time data were evaluated using model independent and dependent methods. RESULTS:Pemetrexed disappearance from plasma was best described by a two compartment model with a mean distribution half-life of 13.8 +/- 3.2 min and an elimination half-life of 70.0 +/- 16.0 min. The volume of distribution of and the clearance from the central compartment were 0.066 +/- 0.017 l/kg and 3.6 +/- 0.6 ml/min/kg, respectively. Peak CSF concentrations occurred 40-71 min after the start of the infusion with an average of 0.26 +/- 0.15 microM. CONCLUSION:The CSF penetration of pemetrexed was less than 2% (range 0.33-1.58%), suggesting that it should be used in conjunction with other CNS preventive strategies when used in the treatment of malignancies with a predilection for CNS or leptomeningeal metastases.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Stapleton SL,Reid JM,Thompson PA,Ames MM,McGovern RM,McGuffey L,Nuchtern J,Dauser R,Blaney SM

doi

10.1007/s00280-006-0285-7

subject

Has Abstract

pub_date

2007-03-01 00:00:00

pages

461-6

issue

4

eissn

0344-5704

issn

1432-0843

journal_volume

59

pub_type

杂志文章

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