The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates
| Autor: | Diane E. Cole, AeRang Kim, Elizabeth Fox, Raphael Cruz, Frank M. Balis, Cindy McCully, Brigitte C. Widemann |
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| Rok vydání: | 2010 |
| Předmět: |
Sorafenib
Male Niacinamide Metabolic Clearance Rate Pyridines Vascular permeability Antineoplastic Agents Pharmacology High-performance liquid chromatography Models Biological Article Pathogenesis Capillary Permeability Cerebrospinal fluid Pharmacokinetics Tandem Mass Spectrometry Medicine Animals Pharmacology (medical) Dosing Infusions Intravenous Protein Kinase Inhibitors Chromatography High Pressure Liquid business.industry Phenylurea Compounds Benzenesulfonates Half-life Macaca mulatta Oncology Blood-Brain Barrier Area Under Curve Models Animal business medicine.drug Half-Life Protein Binding |
| Zdroj: | Investigational new drugs. 30(2) |
| ISSN: | 1573-0646 |
| Popis: | Purpose Sorafenib is a small molecule inhibitor of multiple signaling kinases thought to contribute to the pathogenesis of many tumors including brain tumors. Clinical trials with sorafenib in primary and metastatic brain tumors are ongoing. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of sorafenib after an intravenous (IV) dose in a non-human primate (NHP) model. Methods 7.3 mg/kg of sorafenib free base equivalent solubilized in 20% cyclodextrin was administered IV over 1 h to three adult rhesus monkeys. Serial paired plasma and CSF samples were collected over 24 h. Sorafenib was quantified with a validated HPLC/tandem mass spectrometry assay. PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUCCSF : AUCplasma. Results Peak plasma concentrations after IV dosing ranged from 3.4 to 7.6 μg/mL. The mean ± standard deviation (SD) area under the plasma concentration from 0 to 24 h was 28 ± 4.3 μg•h/mL, which is comparable to the exposure observed in humans at recommended doses. The mean ± SD clearance was 1.7 ± 0.5 mL/min/kg. The peak CSF concentrations ranged from 0.00045 to 0.00058 μg/mL. The mean ± SD area under the CSF concentration from 0 to 24h was 0.0048 ± 0.0016 μg•h/mL. The mean CSF penetration of sorafenib was 0.02% and 3.4% after correcting for plasma protein binding. Conclusion Sorafenib is well tolerated in NHP and measurable in CSF after an IV dose. The CSF penetration of sorafenib is limited relative to total and free drug exposure in plasma. |
| Databáze: | OpenAIRE |
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