Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment.
Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment.
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DOI：
10.1111/cts.12397
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Utay NS
中科院分区：
文献类型：
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作者：
Lefebvre E;Gottwald M;Lasseter K;Chang W;Willett M;Smith PF;Somasunderam A;Utay NS
Cenicriviroc是一种CCR2/CCR5双重拮抗剂，目前正在评估用于治疗非酒精性脂肪性肝炎和肝纤维化（CENTAUR; NCT02217475）。由于它是由肝脏代谢的，我们研究了cenicriviroc在肝脏受损参与者体内的药代动力学变化。轻度至中度肝功能损害（HI） （Child-Pugh A级（N = 7）或B级（N = 8））和匹配对照（N = 15）的参与者接受了150 mg的cenicriviroc治疗，每天一次，持续14天。在第1天和第14天采集了一系列血液样本。评估了安全性、耐受性以及对CCR2/CCR5配体、细胞因子和细菌易位生物标志物的影响。中度HI （AUC0‐τ为55%，Cmax为29%）增加了Cenicriviroc暴露，但轻度HI （AUC0‐τ为38%，Cmax为40%）没有增加。Cenicriviroc耐受性良好。观察到快速有效的CCR2/CCR5阻断，与肝脏炎症或细菌易位生物标志物的增加无关。研究结果表明，cenicriviroc 150mg可用于轻度至中度HI患者。
Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic‐impaired participants for pharmacokinetic changes. Participants with mild‐to‐moderate hepatic impairment (HI) (Child–Pugh class A (N = 7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained on Days 1 and 14. Safety, tolerability, and effects on CCR2/CCR5 ligands, cytokines, and bacterial translocation biomarkers were evaluated. Cenicriviroc exposures were increased by moderate HI (AUC0‐τ 55%, Cmax 29% higher) but were not with mild HI (AUC0‐τ 38%, Cmax 40% lower). Cenicriviroc was well tolerated. Rapid and potent CCR2/CCR5 blockade was observed, not associated with increases in hepatic inflammation or bacterial translocation biomarkers. Study findings suggest that cenicriviroc 150 mg can be used in patients with mild‐to‐moderate HI.