Safety and pharmacokinetics of intrathecal administration of pemetrexed in rats

Cancer Chemother Pharmacol. 2011 Aug;68(2):531-8. doi: 10.1007/s00280-010-1522-7. Epub 2010 Nov 25.

Abstract

Purpose: Leptomeningeal carcinomatosis is a devastating complication of malignant disease. In this study, we evaluated the safety and pharmacokinetics of intrathecally administered pemetrexed in rats.

Methods: Three levels of pemetrexed (0.3, 1, and 3 mg/kg) were administered to 15 rats per level (45 rats in total) twice a week for 2 weeks through specifically designed indwelling subarachnoid catheters. Presence of clinical and pathological neurotoxicity was evaluated. To evaluate the pharmacokinetics of pemetrexed, independent cohorts of 30 rats were treated with 1 mg/kg of pemetrexed and its concentration in cerebrospinal fluid (CSF) and blood was measured using UPLC/MS/MS.

Results: There were no cases of clinical or pathologic neurotoxicity after intrathecal administrations of pemetrexed at levels of 0.3 and 1 mg/kg; however, 5 of 15 (33%) rats died after administration of 3 mg/kg pemetrexed. The distribution/elimination of pemetrexed in CSF was best described by a two-compartment model, with initial and terminal half-lives of 0.43 and 1.43 h, respectively. The predicted maximal concentration in CSF was 588 μM, and high levels of pemetrexed appeared to be maintained for a long time. Area under the curve and volume of distribution at steady state were 560 μM h and 1.14 ml, respectively.

Conclusions: The no observed adverse effect level of intrathecal administration of pemetrexed was 1 mg/kg in rats. At this level, therapeutically high and durable pemetrexed concentrations could be achieved. Based on these results, further research on intrathecal pemetrexed in humans or non-human primates should be considered.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Antimetabolites, Antineoplastic / adverse effects*
  • Antimetabolites, Antineoplastic / analysis
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Catheters, Indwelling
  • Chromatography, High Pressure Liquid
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Glutamates / administration & dosage*
  • Glutamates / adverse effects*
  • Glutamates / analysis
  • Glutamates / pharmacokinetics
  • Guanine / administration & dosage
  • Guanine / adverse effects
  • Guanine / analogs & derivatives*
  • Guanine / analysis
  • Guanine / pharmacokinetics
  • Half-Life
  • Injections, Spinal
  • Male
  • Metabolic Clearance Rate
  • Neurons / drug effects*
  • Neurons / pathology
  • Neurotoxicity Syndromes* / blood
  • Neurotoxicity Syndromes* / cerebrospinal fluid
  • Neurotoxicity Syndromes* / pathology
  • No-Observed-Adverse-Effect Level
  • Pemetrexed
  • Rats
  • Rats, Sprague-Dawley
  • Subarachnoid Space
  • Tandem Mass Spectrometry
  • Tissue Distribution
  • Toxicity Tests

Substances

  • Antimetabolites, Antineoplastic
  • Glutamates
  • Pemetrexed
  • Guanine