Population pharmacokinetic/pharmacodynamic modeling of nifekalant injection with varies dosing plan in Chinese volunteers: a randomized, blind, placebo-controlled study.

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-02-01 Epub Date: 2023-08-11 DOI:10.1007/s10928-023-09882-8
Juanjuan Jiang, Li Xu, Lin Chai, Li Zhang, Hong Liu, Yan Yan, Xiaoyuan Guan, Hui Sun, Lei Tian
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Abstract

Nifekalant hydrochloride is a class III antiarrhythmic agent which could increase the duration of the action potential and the effective refractory period of ventricular and atrial myocytes by blocking the K+ current. Nifekalant is used to prevent ventricular tachycardia/ventricular fibrillation. QT interval prolongation is the main measurable drug effect. However, due to the complicated dosing plan in clinic, the relationship among dosage, time, drug concentration and efficacy is not fully understood. In this study, a single-center, randomized, blind, dose-ascending, placebo-controlled study was conducted to explore the intrinsic characteristics of nifekalant injection in healthy Chinese volunteers by a population pharmacokinetic (PK)-pharmacodynamic (PD) model approach. 42 subjects were enrolled in this study and received one of three dose plans (loading dose on Day 1 (0.15, 0.3 or 0.5 mg/kg), loading dose followed by maintenance dose (0.2, 0.4 or 0.8 mg/kg/h) on Day 4) or vehicle. Blood samples were drawn for PK evaluation, and ECGs were recorded for QTc calculation at the designed timepoints. No Torsades de Pointes occurred during the study. The popPK model of nifekalant injection could be described by a two-compartment model with first-order elimination. The population mean clearance (CL) was 53.8 L/h. The population mean distribution volume of the central (Vc) and peripheral (Vp) compartments was 8.27 L and 45.6 L, respectively. A nonlinear dose-response (Emax) model well described the pharmacodynamic effect (QTc interval prolongation) of nifekalant. The Emax and EC50 from current study were 101 ms and 342 ng/mL, respectively.

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在中国志愿者中采用不同给药方案的硝苯地平注射液的群体药代动力学/药效学模型:一项随机、盲法、安慰剂对照研究。
盐酸奈夫卡兰是一种 III 类抗心律失常药,可通过阻断 K+ 电流延长心室和心房肌细胞的动作电位持续时间和有效折返期。硝苯地平用于预防室性心动过速/室颤。QT 间期延长是可测量的主要药物效应。然而,由于临床用药方案复杂,剂量、时间、药物浓度和疗效之间的关系尚未完全明了。本研究采用群体药代动力学(PK)-药效学(PD)模型方法,在中国健康志愿者中开展了一项单中心、随机、盲法、剂量递增、安慰剂对照研究,以探讨硝苯地平注射液的内在特性。42名受试者参加了这项研究,并接受了三种剂量方案之一(第1天的负荷剂量(0.15、0.3或0.5毫克/千克),第4天的负荷剂量和维持剂量(0.2、0.4或0.8毫克/千克/小时))或药物。抽取血样进行 PK 评估,并在设计的时间点记录心电图以计算 QTc。研究过程中未出现心搏过速现象。硝苯地平注射液的popPK模型可以用一阶消除的二室模型来描述。人群平均清除率(CL)为 53.8 升/小时。中心室(Vc)和外周室(Vp)的群体平均分布容积分别为 8.27 升和 45.6 升。非线性剂量-反应(Emax)模型很好地描述了硝苯地平的药效学效应(QTc间期延长)。本次研究得出的Emax和EC50分别为101毫秒和342纳克/毫升。
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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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