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

Stacie L. Stapleton, Joel M Reid, Patrick A. Thompson, Matthew M. Ames, Renee M. McGovern, Leticia McGuffey, Jed Nuchtern, Robert Dauser, Susan M. Blaney

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)461-466
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume59
Issue number4
DOIs
StatePublished - Mar 2007

Fingerprint

Pemetrexed
Cerebrospinal fluid
Pharmacokinetics
Intravenous Administration
Primates
Cerebrospinal Fluid
Plasmas
Half-Life
Tumors
Animals
Folic Acid Antagonists
Central Nervous System Neoplasms
Pyrimidines
Purines
Neurology
Non-Small Cell Lung Carcinoma
Neoplasms
Blood
Cells
Neoplasm Metastasis

Keywords

  • Antifol
  • Antimetabolite
  • CSF penetration
  • Pemetrexed
  • Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. / Stapleton, Stacie L.; Reid, Joel M; Thompson, Patrick A.; Ames, Matthew M.; McGovern, Renee M.; McGuffey, Leticia; Nuchtern, Jed; Dauser, Robert; Blaney, Susan M.

In: Cancer Chemotherapy and Pharmacology, Vol. 59, No. 4, 03.2007, p. 461-466.

Research output: Contribution to journalArticle

Stapleton, SL, Reid, JM, Thompson, PA, Ames, MM, McGovern, RM, McGuffey, L, Nuchtern, J, Dauser, R & Blaney, SM 2007, 'Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates', Cancer Chemotherapy and Pharmacology, vol. 59, no. 4, pp. 461-466. https://doi.org/10.1007/s00280-006-0285-7
Stapleton, Stacie L. ; Reid, Joel M ; Thompson, Patrick A. ; Ames, Matthew M. ; McGovern, Renee M. ; McGuffey, Leticia ; Nuchtern, Jed ; Dauser, Robert ; Blaney, Susan M. / Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. In: Cancer Chemotherapy and Pharmacology. 2007 ; Vol. 59, No. 4. pp. 461-466.
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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.",
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T1 - Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates

AU - Stapleton, Stacie L.

AU - Reid, Joel M

AU - Thompson, Patrick A.

AU - Ames, Matthew M.

AU - McGovern, Renee M.

AU - McGuffey, Leticia

AU - Nuchtern, Jed

AU - Dauser, Robert

AU - Blaney, Susan M.

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N2 - 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.

AB - 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.

KW - Antifol

KW - Antimetabolite

KW - CSF penetration

KW - Pemetrexed

KW - Pharmacokinetics

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