The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex(TM)) in a nonhuman primate model

Brigitte C. Widemann, Frank M. Balis, Karen S. Godwin, Cindy McCully, Peter C. Adamson

Research output: Contribution to journalArticle

Abstract

Purpose: Raltitrexed (Tomudex(TM)), ZD1694) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase. Intracellularly, raltitrexed is polyglutamated to its active form which can be retained in cells for prolonged periods. The pharmacokinetics of raltitrexed in plasma and cerebrospinal fluid (CSF) were studied in a nonhuman primate model. Methods: Animals received 3 mg/m2 (n = 1), 6 mg/m2 (n = 3), or 10 mg/m2 (n = 3) i.v. over 15 min, and frequent plasma samples were obtained over 48 h. CSF samples were drawn from an indwelling 4th ventricular Ommaya reservoir over 48 h. Plasma and CSF raltitrexed concentrations were measured with a novel, sensitive enzyme inhibition assay with a lower limit of quantification of 0.005 μM. A three-compartment pharmacokinetic model was fitted to the raltitrexed plasma concentration-time data. Results: The plasma concentration-time profile of raltitrexed was triexponential with a rapid initial decline and a prolonged terminal elimination phase (t(1/2) > 24 h), which was related to retention of raltitrexed in a deep tissue compartment. At the peak approximately 30% of the administered dose was in the deep tissue compartment, and 24 h after the dosing > 20% of the administered dose remained in the body with >99% in the deep tissue compartment. The mean peak (end of infusion) plasma concentrations after the 3, 6, and 10 mg/m2 doses were 1.5, 2.4 and 4.8 μM, respectively. The clearance of raltitrexed ranged from 110 to 165 ml/min per m2, and the steady-state volume of distribution exceeded 200 l/m2. The CSF penetration of raltitrexed was limited (0.6 to 2.0%) and drug could only be detected in the CSF following a 10 mg/m2 dose. Conclusions: The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase. The pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexed. The three-compartment model presented here may be useful for the analysis of the pharmacokinetics of raltitrexed in humans.

Original languageEnglish (US)
Pages (from-to)439-443
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume44
Issue number6
DOIs
StatePublished - 1999
Externally publishedYes

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Cerebrospinal fluid
Thymidylate Synthase
Pharmacokinetics
Primates
Cerebrospinal Fluid
Plasmas
Tissue
raltitrexed
Quinazolines
Enzyme inhibition
Enzyme Assays
Folic Acid

Keywords

  • Antifols
  • Enzyme inhibition assay
  • Pharmacokinetic model
  • Thymidylate synthase inhibitor

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex(TM)) in a nonhuman primate model. / Widemann, Brigitte C.; Balis, Frank M.; Godwin, Karen S.; McCully, Cindy; Adamson, Peter C.

In: Cancer Chemotherapy and Pharmacology, Vol. 44, No. 6, 1999, p. 439-443.

Research output: Contribution to journalArticle

Widemann, Brigitte C. ; Balis, Frank M. ; Godwin, Karen S. ; McCully, Cindy ; Adamson, Peter C. / The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex(TM)) in a nonhuman primate model. In: Cancer Chemotherapy and Pharmacology. 1999 ; Vol. 44, No. 6. pp. 439-443.
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abstract = "Purpose: Raltitrexed (Tomudex(TM)), ZD1694) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase. Intracellularly, raltitrexed is polyglutamated to its active form which can be retained in cells for prolonged periods. The pharmacokinetics of raltitrexed in plasma and cerebrospinal fluid (CSF) were studied in a nonhuman primate model. Methods: Animals received 3 mg/m2 (n = 1), 6 mg/m2 (n = 3), or 10 mg/m2 (n = 3) i.v. over 15 min, and frequent plasma samples were obtained over 48 h. CSF samples were drawn from an indwelling 4th ventricular Ommaya reservoir over 48 h. Plasma and CSF raltitrexed concentrations were measured with a novel, sensitive enzyme inhibition assay with a lower limit of quantification of 0.005 μM. A three-compartment pharmacokinetic model was fitted to the raltitrexed plasma concentration-time data. Results: The plasma concentration-time profile of raltitrexed was triexponential with a rapid initial decline and a prolonged terminal elimination phase (t(1/2) > 24 h), which was related to retention of raltitrexed in a deep tissue compartment. At the peak approximately 30{\%} of the administered dose was in the deep tissue compartment, and 24 h after the dosing > 20{\%} of the administered dose remained in the body with >99{\%} in the deep tissue compartment. The mean peak (end of infusion) plasma concentrations after the 3, 6, and 10 mg/m2 doses were 1.5, 2.4 and 4.8 μM, respectively. The clearance of raltitrexed ranged from 110 to 165 ml/min per m2, and the steady-state volume of distribution exceeded 200 l/m2. The CSF penetration of raltitrexed was limited (0.6 to 2.0{\%}) and drug could only be detected in the CSF following a 10 mg/m2 dose. Conclusions: The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase. The pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexed. The three-compartment model presented here may be useful for the analysis of the pharmacokinetics of raltitrexed in humans.",
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T1 - The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex(TM)) in a nonhuman primate model

AU - Widemann, Brigitte C.

AU - Balis, Frank M.

AU - Godwin, Karen S.

AU - McCully, Cindy

AU - Adamson, Peter C.

PY - 1999

Y1 - 1999

N2 - Purpose: Raltitrexed (Tomudex(TM)), ZD1694) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase. Intracellularly, raltitrexed is polyglutamated to its active form which can be retained in cells for prolonged periods. The pharmacokinetics of raltitrexed in plasma and cerebrospinal fluid (CSF) were studied in a nonhuman primate model. Methods: Animals received 3 mg/m2 (n = 1), 6 mg/m2 (n = 3), or 10 mg/m2 (n = 3) i.v. over 15 min, and frequent plasma samples were obtained over 48 h. CSF samples were drawn from an indwelling 4th ventricular Ommaya reservoir over 48 h. Plasma and CSF raltitrexed concentrations were measured with a novel, sensitive enzyme inhibition assay with a lower limit of quantification of 0.005 μM. A three-compartment pharmacokinetic model was fitted to the raltitrexed plasma concentration-time data. Results: The plasma concentration-time profile of raltitrexed was triexponential with a rapid initial decline and a prolonged terminal elimination phase (t(1/2) > 24 h), which was related to retention of raltitrexed in a deep tissue compartment. At the peak approximately 30% of the administered dose was in the deep tissue compartment, and 24 h after the dosing > 20% of the administered dose remained in the body with >99% in the deep tissue compartment. The mean peak (end of infusion) plasma concentrations after the 3, 6, and 10 mg/m2 doses were 1.5, 2.4 and 4.8 μM, respectively. The clearance of raltitrexed ranged from 110 to 165 ml/min per m2, and the steady-state volume of distribution exceeded 200 l/m2. The CSF penetration of raltitrexed was limited (0.6 to 2.0%) and drug could only be detected in the CSF following a 10 mg/m2 dose. Conclusions: The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase. The pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexed. The three-compartment model presented here may be useful for the analysis of the pharmacokinetics of raltitrexed in humans.

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