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 language | English (US) |
|---|---|
| Pages (from-to) | 461-466 |
| Number of pages | 6 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 59 |
| Issue number | 4 |
| DOIs | |
| State | Published - Mar 2007 |
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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 journal › Article
}
TY - JOUR
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.
PY - 2007/3
Y1 - 2007/3
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
UR - http://www.scopus.com/inward/record.url?scp=33846332415&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846332415&partnerID=8YFLogxK
U2 - 10.1007/s00280-006-0285-7
DO - 10.1007/s00280-006-0285-7
M3 - Article
C2 - 16855840
AN - SCOPUS:33846332415
VL - 59
SP - 461
EP - 466
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 4
ER -