Model-based interspecies interpretation of botulinum neurotoxin type A on muscle-contraction inhibition.

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Hyo-Jeong Ryu, Seongsung Kwak, Misun Park, Hwi-Yeol Yun
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引用次数: 0

Abstract

Botulinum neurotoxins (BoNTs) are commonly used in therapeutic and cosmetic applications. One such neurotoxin, BoNT type A (BoNT/A), has been studied widely for its effects on muscle function and contraction. Despite the importance of BoNT/A products, determining the blood concentrations of these toxins can be challenging. To address this, researchers have focused on pharmacodynamic (PD) markers, including compound muscle action potential (CMAP) and digit abduction scoring (DAS). In this study, we aimed to develop a probabilistic kinetic-pharmacodynamic (K-PD) model to interpret CMAP and DAS data obtained from mice and rats during the development of BoNT/A products. The researchers also wanted to gain a better understanding of how the estimated parameters from the model relate to the bridging of animal models to human responses. We used female Institute of Cancer Research mice and Sprague-Dawley (SD) rats to measure CMAP and DAS levels over 32 weeks after administering BoNT/A. We developed a muscle-contraction inhibition model using a virtual pharmacokinetic (PK) compartment combined with an indirect response model and performed model diagnostics using goodness-of-fit analysis, visual predictive checks (VPC), and bootstrap analysis. The CMAP and DAS profiles were dose-dependent, with recovery times varying depending on the administered dose. The final K-PD model effectively characterized the data and provided insights into species-specific differences in the PK and PD parameters. Overall, this study demonstrated the utility of PK-PD modeling in understanding the effects of BoNT/A and provides a foundation for future research on other BoNT/A products.

基于模型的 A 型肉毒杆菌神经毒素对肌肉收缩抑制作用的种间解释。
肉毒杆菌神经毒素(BoNTs)通常用于治疗和美容。其中一种神经毒素,即 BoNT A 型(BoNT/A),因其对肌肉功能和收缩的影响而被广泛研究。尽管 BoNT/A 产品非常重要,但确定这些毒素的血药浓度却很困难。为此,研究人员将重点放在药效学(PD)标记上,包括复合肌肉动作电位(CMAP)和数字外展评分(DAS)。在这项研究中,我们旨在开发一种概率动力学-药效学 (K-PD) 模型,以解释在 BoNT/A 产品开发过程中从小鼠和大鼠身上获得的 CMAP 和 DAS 数据。研究人员还希望更好地了解该模型的估计参数与动物模型和人体反应之间的关系。我们使用癌症研究所的雌性小鼠和 Sprague-Dawley (SD) 大鼠在注射 BoNT/A 后 32 周内测量 CMAP 和 DAS 水平。我们使用虚拟药代动力学 (PK) 区间结合间接反应模型建立了肌肉收缩抑制模型,并使用拟合优度分析、视觉预测检查 (VPC) 和引导分析进行了模型诊断。CMAP 和 DAS 曲线与剂量有关,恢复时间因给药剂量而异。最终的 K-PD 模型有效地描述了数据的特征,并深入揭示了 PK 和 PD 参数的物种特异性差异。总之,这项研究证明了 PK-PD 模型在了解 BoNT/A 作用方面的实用性,并为今后研究其他 BoNT/A 产品奠定了基础。
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来源期刊
CiteScore
3.60
自引率
0.00%
发文量
35
审稿时长
6-12 weeks
期刊介绍: Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes: - animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites, - in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man - studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition, - simulation and modeling in drug discovery and development - theoretical treatises - includes themed issues and reviews and exclude manuscripts on - bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation - analytical methods
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