, Volume 59, Issue 4, pp 461-466
Date: 20 Jul 2006

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

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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.