Abstract
Purpose Imatinib mesylate (Gleevec, imatinib) is a potent tyrosine kinase inhibitor that is currently approved for treatment of CML and GIST and is being evaluated for treatment of malignant gliomas and other solid tumors. We used a nonhuman primate model that is highly predictive of CNS drug penetration in humans to study the pharmacokinetics of imatinib in plasma and 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 HPLC. 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 plasma AUC 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. Following i.v. dosing the VDss was 5.9 ± 2.8 L/kg and the ClTB 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 AUC ratio was 5 ± 2%. Conclusions There is limited penetration of imatinib into the CSF of nonhuman primates. Thus, consideration must be given to development of appropriate strategies for prevention and treatment CNS relapses in patients treated with imatinib. Clinical Pharmacology & Therapeutics (2004) 75, P59–P59; doi: 10.1016/j.clpt.2003.11.223
Published Version
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