A population pharmacokinetics model of balovaptan to support dose selection in adult and pediatric populations

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-02-03 DOI:10.1007/s10928-023-09898-0
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Abstract

Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population pharmacokinetic (PK) model of balovaptan was developed, initially to assist clinical dosing for adult and pediatric ASD studies and subsequently for new clinical indications including malignant cerebral edema (MCE) and post-traumatic stress disorder. The final model incorporates one-compartment disposition and describes time- and dose-dependent non-linear PK through empirical drug binding and a gut extraction component with turnover. An age effect on clearance observed in children was modeled by an asymptotic function that predicts adult-equivalent exposures at 40% of the adult dose for children aged 2–4 years, 70% for 5–9 years, and at the full adult dose for ≥ 10 years. The model was adapted for intravenous (IV) balovaptan dosing and combined with in vitro and ex vivo pharmacodynamic data to simulate brain receptor occupancy as a guide for dosing in a phase II trial of MCE prophylaxis after acute ischemic stroke. A sequence of three stepped-dose daily infusions of 50, 25 and 15 mg over 30 or 60 min was predicted to achieve a target occupancy of ≥ 80% in ≥ 95% of patients over a 3-day period. This model predicts both oral and IV balovaptan exposure across a wide age range and will be a valuable tool to analyze and predict its PK in new indications and target populations, including pediatric patients.

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支持成人和儿童剂量选择的巴络伐坦群体药代动力学模型
摘要 巴络伐坦是一种脑穿透性血管加压素受体1a拮抗剂,以前曾针对自闭症谱系障碍(ASD)的核心症状进行过研究。我们开发了巴络伐坦的群体药代动力学(PK)模型,最初是为了协助成人和儿童自闭症谱系障碍研究的临床用药,后来又用于新的临床适应症,包括恶性脑水肿(MCE)和创伤后应激障碍。最终模型采用了单室处置,并通过经验药物结合和肠道提取成分与周转来描述时间和剂量依赖性非线性 PK。该模型预测 2-4 岁儿童的成人等效暴露量为成人剂量的 40%,5-9 岁为 70%,≥ 10 岁为成人全剂量。该模型适用于静脉注射(IV)巴洛伐坦,并与体外和体内药效学数据相结合,模拟脑受体的占用率,作为急性缺血性脑卒中后MCE预防II期试验的剂量指南。据预测,在 30 或 60 分钟内,每天分三次阶梯输注 50、25 和 15 毫克,3 天内可使≥ 95% 的患者达到≥ 80% 的目标占位率。该模型可预测各年龄段的口服和静脉注射巴络伐坦暴露量,将成为分析和预测其在新适应症和目标人群(包括儿科患者)中的PK值的重要工具。
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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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