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
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
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DOI：
10.1124/dmd.108.021931
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发表时间：
2009-03
影响因子：
3.9
通讯作者：
G. Tonn;Simon G. Wong;Sylvia C. Wong;Michael G. Johnson;Ji Ma;Robert Cho;L. Floren;K. Kersey;Karen Berry;Andrew P. Marcus;Xuemei Wang;Bettina van Lengerich;J. Medina;P. Pearson;B. Wong
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文献类型：
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作者：
G. Tonn;Simon G. Wong;Sylvia C. Wong;Michael G. Johnson;Ji Ma;Robert Cho;L. Floren;K. Kersey;Karen Berry;Andrew P. Marcus;Xuemei Wang;Bettina van Lengerich;J. Medina;P. Pearson;B. Wong
（R）-N-{1-[3-（4-乙氧基-苯基）-4-氧代-3，4-二氢-吡啶并[2，3-d]-嘧啶-2-基]-乙基}-N-吡啶-3-基-甲基-2-（4-三氟甲氧基苯基）-乙酰胺（AMG 487）是一种强效和选择性口服生物可利用趋化因子（C-X-C基序）受体3（CXCR 3）拮抗剂，在人类受试者中多次口服给药后显示剂量和时间依赖性药代动力学。尽管AMG 487在25 mg剂量下在第1天和第7天均表现出线性药代动力学，但在两个较高剂量下，剂量和时间依赖性动力学明显。多次给药后，非线性动力学更加明显。与第1天AUC（0-24 h）增加28倍相比，第7天剂量增加10倍时，0 - 24 h血药浓度-时间曲线下面积[AUC（0-24 h）]增加96倍。这些变化与代谢产物相对于母体药物血浆浓度的时间和剂量依赖性降低相关，表明这些变化是由于AMG 487的口服清除率（CL）降低所致（例如，肠/肝首过代谢和全身CL）。AMG 487的生物转化依赖于CYP 3A，并导致形成两种主要代谢产物：吡啶基N-氧化物AMG 487（M1）和O-脱乙基AMG 487（M2）。其中一种代谢产物M2通过CYP 3A进一步代谢。还证明了M2以竞争性（Ki = 0.75 μM）方式以及通过基于机制的抑制（未结合KI = 1.4 μM，kinact = 0.041 min-1）抑制CYP 3A。本研究的数据表明，M2介导的基于CYP 3A机制的抑制是AMG 487时间依赖性药代动力学的近端原因。然而，M2的顺序代谢、非线性AMG 487药代动力学以及无法准确确定肠道AMG 487代谢的作用使得M2血浆浓度与时间依赖性AMG 487药代动力学变化之间的相关性复杂化。
(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 (Ki = 0.75 μM) manner as well as via mechanism-based inhibition (unbound KI = 1.4 μM, kinact = 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.