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Plasma and Cerebrospinal Fluid Pharmacokinetics of Imatinib after Administration to Nonhuman Primates

¹ Texas Children’s Cancer Center and ² Department of Pediatrics, Baylor College of Medicine, Houston, Texas; ³ Program of Molecular Therapeutics and Drug Discovery, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; ⁴ Departments of Medicine and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and ⁵ The Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland

Purpose: Imatinib mesylate (Gleevec, Glivec, STI571, imatinib) is a potent tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. The role of imatinib in the treatment of malignant gliomas and other solid tumors is being evaluated. We used a nonhuman primate model that is highly predictive of the cerebrospinal fluid penetration of drugs in humans to study the pharmacokinetics of imatinib in plasma and cerebrospinal fluid (CSF) after i.v. and p.o. administration.

Experimental Design: Imatinib, 15 mg/kg i.v. over 30 min (n = 3) or 30 mg/kg p.o. (n = 3), was administered to nonhuman primates. Imatinib was measured in serial samples of plasma and CSF using high-pressure liquid chromatography with UV absorbance or mass spectroscopic detection. Pharmacokinetic parameters were estimated using model-independent methods.

Results: Peak plasma imatinib concentrations ranged from 6.4 to 9.5 µM after i.v. dosing and 0.8 to 2.8 µM after p.o. dosing. The mean ±SD area under the plasma concentration versus time curve was 2480 ±1340 µM·min and 1191 ±146 µM·min after i.v. and p.o. dosing, respectively. The terminal half-life was 529 ±167 min after i.v. dosing and 266 ±88 min after p.o. dosing. After i.v. dosing the steady state volume of distribution was 5.9 ±2.8 liter/kg, and the total body clearance was 12 ±5 ml/min/kg. The mean peak CSF concentration was 0.25 ±0.07 µM after i.v. dosing and 0.07 ±0.04 µM after p.o. dosing. The mean CSF:plasma area under the plasma concentration versus time curve ratio for all of the animals was 5% ±2%.

Conclusions: There is limited penetration of imatinib into the CSF of nonhuman primates after i.v. and p.o. administration.

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