Target-mediated metabolism and target-mediated drug disposition of the DPPIV inhibitor AMG 222

1. Pharmacokinetic and metabolism aspects of AMG 222 interaction with target enzyme, dipeptidylpeptidase IV (DPPIV) were investigated.

2. Inhibition of recombinant human DPPIV by AMG 222 was measured. IC₅₀ decreased as preincubation time increased. k_off, k_on and K_d were measured. Dilution assay indicated a long dissociation half-life (730?min) relative to DPPIV inhibitor vildagliptin. AMG 222 is a slow-on, tight-binding, slowly reversible inhibitor of DPPIV.

3. Amide and acid metabolites arising from hydrolysis of AMG 222’s cyano group were formed slowly by rhDPPIV, but not by microsomes or S9. The amide metabolite was converted to the acid metabolite by rhDPPIV, but not by an active site mutant. These metabolites of AMG 222 are formed by target-mediated metabolism of the cyano group, similar to vildagliptin.

4. Human plasma protein binding of ¹⁴C]AMG 222 was saturable and concentration-dependent. After 30?min, ¹⁴C]AMG 222 was 80.8% bound at 1?nM and binding decreased to 29.4% above 100?nM. The plasma DPPIV concentration (4.1?nM) and human plasma AMG 222 concentrations that inhibit DPPIV, occurred in the range of concentration-dependent binding. Target-mediated drug disposition influences AMG 222 pharmacokinetics, similar to DPPIV inhibitor, linagliptin.