Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates
Cancer Chemotherapy and Pharmacology. 2006 Jul 20; [Epub ahead of print] [Link]
Stacie L. Stapleton1, Joel M. Reid2, Patrick A. Thompson1, Matthew M. Ames2, Renee M. McGovern2, Leticia McGuffey1, Jed Nuchtern3, Robert Dauser4 and Susan M. Blaney1
(1) Texas Children’s Cancer Center, Baylor College of Medicine, 6621 Fannin, CC 1410.00, Houston, TX 77030, USA
(2) Mayo Clinic, Rochester, MN 55905, USA
(3) Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
(4) Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA
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.
Keywords: Pemetrexed – Antifol – Antimetabolite – CSF penetration – Pharmacokinetics
