Abstract
Purpose:
To investigate the pharmacokinetics, pharmacodynamics and metabolism of the novel matrix metalloproteinase (MMP) inhibitor ABT-518.
Methods:
Plasma and urine samples were obtained from six patients included in a phase I trial in which ABT-518 was given once daily via the oral route. Samples were analyzed by LC-MS/MS, ELISA and immunocapture assay. The pharmacokinetics of the parent compound and of detectable metabolites were calculated.
Results:
After a single dose of ABT-518 peak plasma levels were reached within 4-8 h. ABT-518 had an estimated clearance (Cl/F) of approximately 3 l/h, an estimated volume of distribution (V/F) of over 70 l and a terminal half-life (T(1/2)) of 20 h. At least six different metabolites were formed. Pharmacodynamic analysis for angiogenic growth factors (bFGF and VEGF) showed plasma and urine levels in the picogram range and for total MMP-9 and MMP-2 or MMP-9 activity showed plasma and urine levels in the nanogram range.
Conclusions:
The MMP inhibitor ABT-518 is extensively metabolized in humans. No significant correlations between pharmacokinetics and pharmacodynamics could be established.
Publication types
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Clinical Trial
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Clinical Trial, Phase I
MeSH terms
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Adult
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Aged
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Chromatography, High Pressure Liquid
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Endothelial Growth Factors / blood
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Endothelial Growth Factors / urine
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacokinetics*
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Enzyme Inhibitors / pharmacology*
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Enzyme-Linked Immunosorbent Assay
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Female
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Fibroblast Growth Factor 2 / blood
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Fibroblast Growth Factor 2 / urine
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Formamides / metabolism
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Formamides / pharmacokinetics*
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Formamides / pharmacology*
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Half-Life
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Humans
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Intercellular Signaling Peptides and Proteins / blood
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Intercellular Signaling Peptides and Proteins / urine
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Lymphokines / blood
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Lymphokines / urine
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Mass Spectrometry
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Matrix Metalloproteinase Inhibitors*
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Maximum Tolerated Dose
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Metabolic Clearance Rate
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Middle Aged
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Neoplasms / drug therapy
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Neoplasms / metabolism*
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Enzyme Inhibitors
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Formamides
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Matrix Metalloproteinase Inhibitors
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N-(1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-((4,4-(trifluoromethoxyphenoxy)phenyl)sulfonyl)ethyl)-N-hydroxyformamide
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Fibroblast Growth Factor 2