title: 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.
abstract: 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.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen, Inc, 1201 Amgen Court West, Mail Stop AW2/D3205, Seattle, WA 98119, USA. rfoti@amgen.com
authors.forename: Robert S
authors.initials: RS
authors.lastname: Foti
authors.forename: Josh T
authors.initials: JT
authors.lastname: Pearson
authors.forename: Simon L
authors.initials: SL
authors.lastname: Wong
authors.forename: Julie A
authors.initials: JA
authors.lastname: Zalikowski
authors.forename: Michael D
authors.initials: MD
authors.lastname: Boudreaux
authors.forename: Samantha P
authors.initials: SP
authors.lastname: Prokop
authors.forename: John A
authors.initials: JA
authors.lastname: Davis
authors.forename: Christopher
authors.initials: C
authors.lastname: Banfield
authors.forename: Maurice G
authors.initials: MG
authors.lastname: Emery
authors.forename: Dan A
authors.initials: DA
authors.lastname: Rock
authors.forename: Jan L
authors.initials: JL
authors.lastname: Wahlstrom
authors.forename: Larry C
authors.initials: LC
authors.lastname: Wienkers
authors.forename: Benny M
authors.initials: BM
authors.lastname: Amore
mesh_terms: D000293:Adolescent; D000328:Adult; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008875:Middle Aged; D010648:Phenylacetates / Q000494:pharmacology*; D011453:Prostaglandins / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D010648:Phenylacetates; D011453:Prostaglandins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C400322:cytochrome P-450 CYP2C subfamily; C573852:vidupiprant; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D007654:Ketoconazole; C036293:prostaglandin D2 receptor