title: An inhibitory metabolite leads to dose- and time-dependent pharmacokinetics of (R)-N-{1-[3-(4-ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxy-phenyl)-acetamide (AMG 487) in human subjects after multiple dosing.
abstract: (R)-N-{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]-pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxyphenyl)-acetamide (AMG 487) is a potent and selective orally bioavailable chemokine (C-X-C motif) receptor 3 (CXCR3) antagonist that displays dose- and time-dependent pharmacokinetics in human subjects after multiple oral dosing. Although AMG 487 exhibited linear pharmacokinetics on both days 1 and 7 at the 25-mg dose, dose- and time-dependent kinetics were evident at the two higher doses. Nonlinear kinetics were more pronounced after multiple dosing. Area under the plasma concentration-time curve from 0 to 24 h [AUC((0-24 h))] increased 96-fold with a 10-fold increase in dose on day 7 compared with a 28-fold increase in AUC((0-24 h)) on day 1. These changes were correlated with time- and dose-dependent decreases in the metabolite to parent plasma concentrations, suggesting that these changes result from a decrease in the oral clearance (CL) of AMG 487 (e.g., intestinal/hepatic first-pass metabolism and systemic CL). The biotransformation of AMG 487 is dependent on CYP3A and results in the formation of two primary metabolites, a pyridyl N-oxide AMG 487 (M1) and an O-deethylated AMG 487 (M2). One of these metabolites, M2, undergoes further metabolism by CYP3A. M2 has also been demonstrated to inhibit CYP3A in a competitive (K(i)=0.75 microM) manner as well as via mechanism-based inhibition (unbound K(I)=1.4 microM, k(inact)=0.041 min(-1)). Data from this study implicate M2-mediated CYP3A mechanism-based inhibition as the proximal cause for the time-dependent pharmacokinetics of AMG 487. However, the sequential metabolism of M2, nonlinear AMG 487 pharmacokinetics, and the inability to accurately determine the role of intestinal AMG 487 metabolism complicates the correlation between M2 plasma concentrations and the time-dependent AMG 487 pharmacokinetic changes.
authors.affiliation: Department of Pharmacokinetics, Amgen Inc., South San Francisco, California, USA. george.tonn@elan.com
authors.forename: George R
authors.initials: GR
authors.lastname: Tonn
authors.forename: Simon G
authors.initials: SG
authors.lastname: Wong
authors.forename: Sylvia C
authors.initials: SC
authors.lastname: Wong
authors.forename: Michael G
authors.initials: MG
authors.lastname: Johnson
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Robert
authors.initials: R
authors.lastname: Cho
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Floren
authors.forename: Kathryn
authors.initials: K
authors.lastname: Kersey
authors.forename: Karen
authors.initials: K
authors.lastname: Berry
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Marcus
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Bettina
authors.initials: B
authors.lastname: Van Lengerich
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.forename: Paul G
authors.initials: PG
authors.lastname: Pearson
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Wong
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D002853:Chromatography, Liquid; D015331:Cohort Studies; D065607:Cytochrome P-450 Enzyme Inhibitors; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry
chemical_list: D000081:Acetamides; C515187:CXCR3 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; C541505:N-(1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido(2,3-d)pyrimidin-2-yl)ethyl)-N-pyridin-3-ylmethyl-2-(4-trifluoromethoxyphenyl)acetamide; D011744:Pyrimidinones; D054367:Receptors, CXCR3