Population pharmacokinetics of the dual endothelin receptor antagonist aprocitentan in subjects with or without essential or resistant hypertension.

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Janneke M Brussee, Patricia N Sidharta, Jasper Dingemanse, Andreas Krause
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引用次数: 0

Abstract

Aprocitentan is a novel, potent, dual endothelin receptor antagonist that recently demonstrated efficacy in the treatment of difficult-to-treat (resistant) hypertension. The aim of this study was to develop a population pharmacokinetic (PK) model describing aprocitentan plasma concentration over time, to investigate relationships between subject-specific factors (covariates) and model parameters, and to quantify the influence of the identified covariates on the exposure to aprocitentan via model-based simulations, enabling judgment about the clinical relevance of the covariates.PK data from 902 subjects in ten Phase 1, one Phase 2, and one Phase 3 study were pooled to develop a joint population PK model. The concentration-time course of aprocitentan was described by a two-compartment model with absorption lag time, first-order absorption and elimination, and reduced relative bioavailability following very high doses of 300 and 600 mg.The population PK model described the observed data well. Volume and clearance parameters were associated with body weight. Renal function as reflected by estimated glomerular filtration rate (eGFR), hepatic impairment, and sex were identified as relevant covariates on clearance.The subject-specific characteristics of body weight, eGFR, hepatic impairment, and sex were shown to influence exposure parameters area under the concentration-time curve and maximum concentration in steady state to a limited extent, i.e., not more than 25% different from a reference subject, and therefore do not warrant dose adjustments.

Abstract Image

双重内皮素受体拮抗剂阿普西坦在患有或不患有原发性或抵抗性高血压受试者中的群体药代动力学。
阿普西坦是一种新型、强效、双重内皮素受体拮抗剂,最近在治疗难治性(抵抗性)高血压方面显示出疗效。本研究旨在建立一个描述阿普西坦血浆浓度随时间变化的群体药代动力学(PK)模型,研究受试者特异性因素(协变量)与模型参数之间的关系,并通过基于模型的模拟量化已确定的协变量对阿普西坦暴露的影响,从而判断协变量的临床相关性。阿普西坦的血药浓度-时间过程由一个两室模型描述,该模型具有吸收滞后时间、一阶吸收和消除,以及在服用 300 毫克和 600 毫克的超大剂量后相对生物利用度降低的特点。容量和清除率参数与体重有关。体重、肾小球滤过率(eGFR)、肝功能损害和性别等受试者特异性特征对暴露参数浓度-时间曲线下面积和稳态最大浓度的影响有限,即与参照受试者的差异不超过 25%,因此不需要调整剂量。
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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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