非索罗定在小儿神经源性逼尿肌过度活跃患者中的群体药代动力学和药效学模型。

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Yamato Sano, Satoshi Shoji, Mohamed Shahin, Kevin Sweeney, Amanda Darekar, Bimal K Malhotra
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引用次数: 0

摘要

背景和目的:非索特罗定是一种毒蕈碱受体拮抗剂,被批准用于治疗成人膀胱过动症(OAB)和小儿神经源性逼尿肌过动症(NDO)。本研究旨在描述5-羟甲基托特罗定(5-HMT, fesoterodine的活性代谢物)在小儿OAB或NDO患者服用fesoterodine后的群体药代动力学及其药代动力学/药效学关系。方法:对142名年龄≥6岁的受试者进行5-HMT血药浓度分析,建立非线性混合效应模型。使用最终模型进行基于体重的5-HMT暴露和最大膀胱容量(MCC)模拟。结果:考虑体重、性别、细胞色素(CYP) 2D6代谢状态和非索特罗定配方对5-HMT药动学参数影响的一阶吸收和滞后时间的单室模型最能描述5-HMT药动学参数。Emax模型充分描述了暴露-反应关系。据估计,体重25-35 kg且每日服用一次8mg (QD)的儿科患者在稳定状态下的最大中位数浓度是每日服用8mg (QD)的成人的2.45倍。此外,模拟结果显示,体重25-35 kg的儿童患者每日给予fesoterodine 4mg,体重>35 kg的儿童患者每日给予fesoterodine 8mg,可以获得足够的剂量,以证明与基线(CFB) MCC相比有临床意义的变化。结论:建立了儿童患者5-HMT和MCC的群体模型。基于体重的模拟表明,体重为25-35 kg的儿科患者服用4 mg QD,体重> 35 kg的儿童服用8 mg QD,其暴露量与服用8 mg QD和临床意义的CFB MCC的成人相似。临床试验编号:NCT00857896、NCT01557244。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Population Pharmacokinetic and Pharmacodynamic Modeling of Fesoterodine in Pediatric Patients with Neurogenic Detrusor Overactivity.

Population Pharmacokinetic and Pharmacodynamic Modeling of Fesoterodine in Pediatric Patients with Neurogenic Detrusor Overactivity.

Population Pharmacokinetic and Pharmacodynamic Modeling of Fesoterodine in Pediatric Patients with Neurogenic Detrusor Overactivity.

Population Pharmacokinetic and Pharmacodynamic Modeling of Fesoterodine in Pediatric Patients with Neurogenic Detrusor Overactivity.

Background and objective: Fesoterodine is a muscarinic receptor antagonist approved for the treatment of overactive bladder (OAB) in adults and neurogenic detrusor overactivity (NDO) in pediatric patients. This work aimed to characterize the population pharmacokinetics of 5-hydroxymethyl tolterodine (5-HMT, the active metabolite of fesoterodine) and its pharmacokinetic/pharmacodynamic relationship in pediatric patients with OAB or NDO following administration of fesoterodine.

Methods: 5-HMT plasma concentrations from 142 participants of age ≥ 6 years were analyzed, and a nonlinear mixed-effects model was developed. Weight-based simulations of 5-HMT exposure and maximum cystometric capacity (MCC) were conducted using the final models.

Results: A one-compartment model with first-order absorption and a lag time, which included the effects of body weight, sex, cytochrome (CYP) 2D6 metabolizer status and fesoterodine formulation on pharmacokinetic parameters, best described the 5-HMT pharmacokinetics. An Emax model described the exposure-response relationship adequately. The median maximum concentration at steady state for pediatric patients weighing 25-35 kg and receiving 8 mg once daily (QD) was estimated to be 2.45 times greater than that in adults receiving 8 mg QD. Furthermore, simulation results showed dosing with fesoterodine 4 mg QD to pediatric patients weighing 25-35 kg and 8 mg QD to pediatric patients weighing >35 kg would achieve adequate exposure to demonstrate a clinically meaningful change from baseline (CFB) MCC.

Conclusions: Population models were developed for 5-HMT and MCC in pediatric patients. Weight-based simulations indicated that 4 mg QD for pediatric patients weighing 25-35 kg and 8 mg QD for those weighing > 35 kg provided similar exposures to those in adults following 8 mg QD and a clinically meaningful CFB MCC.

Clinical trial numbers: NCT00857896, NCT01557244.

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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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