Predicting the Drug Interaction Potential of AMG 853, a Dual Antagonist of the D-Prostanoid and Chemoattractant Receptor-Homologous Molecule Expressed on T Helper 2 Cells Receptors

AMG 853 is an orally bioavailable and potent dual antagonist of the D-prostanoid (DP) and chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) receptors. The drug interaction potential of AMG 853, both as a victim and perpetrator, was investigated using in vitro , in silico and in vivo methodologies. Experiments in human liver microsomes (HLM) and recombinant enzymes identified CYP2C8, CYP2J2 and CYP3A as well as multiple UGT isoforms as being responsible for the metabolic clearance of AMG 853. Using HLM and selective probe substrates, both AMG 853 and its acyl glucuronide metabolite (M1) were shown to be inhibitors of CYP2C8. AMG 853 and M1 did not inhibit any of the other CYP isoforms tested and AMG 853 exhibited minimal enzyme induction properties in human hepatocytes cultures. In light of the in vitro findings, modeling and simulation approaches were utilized to examine the potential for ketoconazole (a CYP3A inhibitor) to inhibit the metabolism of AMG 853 as well as for AMG 853 to inhibit the metabolism of paclitaxel, rosiglitazone and montelukast, commonly used substrates of CYP2C8. A weak and clinically insignificant drug interaction (AUCi/AUC < 2) was predicted between ketoconazole and AMG 853. No drug interactions were predicted for AMG 853 and paclitaxel, rosiglitazone or montelukast. Finally, administration of AMG 853 to healthy human subjects in clinical trials in the presence or absence of ketoconazole confirmed that AMG 853 is unlikely to be involved in clinically significant drug interactions.