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

Stacie L. Stapleton, Joel M. Reid, Patrick A. Thompson, Matthew M. Ames, Renee M. McGovern, Leticia McGuffey, Jed Nuchtern, Robert Dauser, Susan M. Blaney

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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 μM. 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.

Original languageEnglish (US)
Pages (from-to)461-466
Number of pages6
JournalCancer chemotherapy and pharmacology
Volume59
Issue number4
DOIs
StatePublished - Mar 2007

Keywords

  • Antifol
  • Antimetabolite
  • CSF penetration
  • Pemetrexed
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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