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

Cancer Chemother Pharmacol. 2007 Mar;59(4):461-6. doi: 10.1007/s00280-006-0285-7. Epub 2006 Jul 20.


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.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Area Under Curve
  • Folic Acid Antagonists / pharmacokinetics*
  • Glutamates / administration & dosage
  • Glutamates / pharmacokinetics*
  • Guanine / administration & dosage
  • Guanine / analogs & derivatives*
  • Guanine / pharmacokinetics
  • Half-Life
  • Infusions, Intravenous
  • Macaca mulatta
  • Pemetrexed
  • Protein Binding


  • Antimetabolites, Antineoplastic
  • Folic Acid Antagonists
  • Glutamates
  • Pemetrexed
  • Guanine