Clinical pharmacokinetics, pharmacodynamics and metabolism of the novel matrix metalloproteinase-inhibitor AHT-518

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 1/h, an estimated volume of distribution (V/F) of over 70 1 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.