RT Journal Article
SR Electronic
T1 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
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2239
OP 2249
DO 10.1124/dmd.112.047928
VO 40
IS 12
A1 Robert S. Foti
A1 Josh T. Pearson
A1 Simon L. Wong
A1 Julie A. Zalikowski
A1 Michael D. Boudreaux
A1 Samantha P. Prokop
A1 John A. Davis
A1 Christopher Banfield
A1 Maurice G. Emery
A1 Dan A. Rock
A1 Jan L. Wahlstrom
A1 Larry C. Wienkers
A1 Benny M. Amore
YR 2012
UL http://dmd.aspetjournals.org/content/40/12/2239.abstract
AB 2-(4-(4-(tert-Butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenylsulfonamido)phenoxy)-5-chloro-2-fluorophenyl)acetic acid (AMG 853) is an orally bioavailable and potent dual antagonist of the D-prostanoid and chemoattractant receptor-homologous molecule expressed on T helper 2 cells receptors. The drug interaction potential of AMG 853, both as a victim and a 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 UDP-glucuronosyltransferase isoforms as being responsible for the metabolic clearance of AMG 853. With use of 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 cytochrome P450 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 used 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 (area under the drug concentration-time curve (AUC)i/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.