Bui Khanh, She Fahua, Sostek Mark
AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
J Clin Pharmacol. 2014 Dec;54(12):1368-74. doi: 10.1002/jcph.348. Epub 2014 Jun 27.
Naloxegol is a peripherally acting µ-opioid receptor antagonist (PAMORA) in development for the treatment of opioid-induced constipation (OIC). The pharmacokinetics of a single oral 25-mg dose of naloxegol in plasma was assessed in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment and compared with healthy volunteers. Participants were matched for sex, age, and body mass index. Hepatically impaired patients exhibited a 17%-18% decrease in area under the plasma concentration versus time curve (AUC) despite similar maximum plasma concentrations (Cmax ). This was an unexpected finding given that naloxegol is primarily cleared by the hepatic route. Time to Cmax was shorter in patients with moderate impairment (0.6 hours) versus those with mild impairment (2.3 hours) or normal subjects (2.0 hours). Mean apparent terminal half-life (t½ ) was shorter in patients with mild (9.6 hours) and moderate (7.5 hours) hepatic impairment versus healthy subjects (11.3 hours). Reductions in enterohepatic recycling of naloxegol because of hepatic impairment may explain the observed decreases in AUC and t½ observed in these patients. Naloxegol was generally well tolerated, and mild or moderate hepatic impairment appeared to have minimal effect on its pharmacokinetics and safety.
纳洛西戈是一种正在研发的外周作用的μ阿片受体拮抗剂（PAMORA），用于治疗阿片类药物引起的便秘（OIC）。在轻度（Child-Pugh A级）或中度（Child-Pugh B级）肝功能损害患者中评估了单次口服25 mg剂量纳洛西戈在血浆中的药代动力学，并与健康志愿者进行了比较。参与者在性别、年龄和体重指数方面进行了匹配。尽管最大血浆浓度（Cmax）相似，但肝功能受损患者的血浆浓度-时间曲线下面积（AUC）下降了17%-18%。鉴于纳洛西戈主要通过肝脏途径清除，这是一个意外发现。中度肝功能损害患者达到Cmax的时间（0.6小时）比轻度肝功能损害患者（2.3小时）或正常受试者（2.0小时）短。轻度（9.6小时）和中度（7.5小时）肝功能损害患者的平均表观终末半衰期（t½）比健康受试者（11.3小时）短。肝功能损害导致纳洛西戈肝肠循环减少，可能解释了这些患者中观察到的AUC和t½下降。纳洛西戈总体耐受性良好，轻度或中度肝功能损害似乎对其药代动力学和安全性影响最小。
