Clinical pharmacokinetics, pharmacodynamics and metabolism of the novel matrix metalloproteinase inhibitor ABT-518.
OBJECTIVE
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.
Crul
Mirjam
M
Slotervaart Hospital, Department of Pharmacy and Pharmacology, Amsterdam, The Netherlands. apmcr@slz.nl
Beerepoot
Laurens V
LV
Stokvis
Ellen
E
Vermaat
Johannes S P
JS
Rosing
Hilde
H
Beijnen
Jos H
JH
Voest
Emile E
EE
Schellens
Jan H M
JH
D000328:Adult; D000368:Aged; D002851:Chromatography, High Pressure Liquid; D016228:Endothelial Growth Factors / Q000097:blood / Q000652:urine; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood / Q000652:urine; D005559:Formamides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000652:urine; D008222:Lymphokines / Q000097:blood / Q000652:urine; D013058:Mass Spectrometry; D061965:Matrix Metalloproteinase Inhibitors; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D005559:Formamides; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D061965:Matrix Metalloproteinase Inhibitors; C443806:N-(1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-((4,4-(trifluoromethoxyphenoxy)phenyl)sulfonyl)ethyl)-N-hydroxyformamide; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2