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


CONCLUSIONS
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.
Stapleton
Stacie L
SL
Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin, CC 1410.00, Houston, TX 77030, USA. slstaple@txccc.org
Reid
Joel M
JM
Thompson
Patrick A
PA
Ames
Matthew M
MM
McGovern
Renee M
RM
McGuffey
Leticia
L
Nuchtern
Jed
J
Dauser
Robert
R
Blaney
Susan M
SM
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics*; D005971:Glutamates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006207:Half-Life; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D000068437:Pemetrexed; D011485:Protein Binding
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine