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.
摘要：
肉毒杆菌神经毒素(BoNT)通常用于治疗和美容应用。一种这样的神经毒素，BoNTA型(BoNT/A),已广泛研究其对肌肉功能和收缩的影响。尽管BoNT/A产品的重要性，确定这些毒素的血液浓度可能具有挑战性。为了解决这个问题，研究人员专注于药效学（PD）标记，包括复合肌肉动作电位（CMAP）和手指外展评分（DAS）。在这项研究中,我们的目的是建立一个概率动力学-药效学(K-PD)模型,以解释BoNT/A产品开发过程中从小鼠和大鼠获得的CMAP和DAS数据.研究人员还希望更好地了解模型中的估计参数如何与动物模型与人类反应的桥接有关。我们使用雌性癌症研究所小鼠和Sprague-Dawley（SD）大鼠在施用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）室结合间接反应模型开发了肌肉收缩抑制模型，并使用拟合优度分析进行了模型诊断。视觉预测检查(VPC)，和引导分析。CMAP和DAS曲线呈剂量依赖性，恢复时间取决于给药剂量。最终的K-PD模型有效地表征了数据，并提供了对PK和PD参数中物种特异性差异的见解。总的来说,这项研究证明了PK-PD模型在理解BoNT/A的作用方面的实用性，并为其他BoNT/A产品的未来研究提供了基础。
