Ryu Hyo-Jeong, Kwak Seongsung, Park Misun, Yun Hwi-Yeol
Department of Pharmacology and Toxicology, Gwangyo R&D Center, Medytox Inc., Suwon, South Korea.
College of Pharmacy, Chungnam National University, Daejeon, South Korea.
Biopharm Drug Dispos. 2024 Dec;45(4-6):190-200. doi: 10.1002/bdd.2398. Epub 2024 Jul 19.
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.
肉毒杆菌神经毒素（BoNTs）常用于治疗和美容领域。其中一种神经毒素，A型肉毒杆菌神经毒素（BoNT/A），因其对肌肉功能和收缩的影响而受到广泛研究。尽管BoNT/A产品很重要，但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）标志物，包括复合肌肉动作电位（CMAP）和手指外展评分（DAS）。在本研究中，我们旨在开发一种概率性动力学-药效学（K-PD）模型，以解释在BoNT/A产品研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估计参数与动物模型到人类反应的桥接之间的关系。我们使用雌性癌症研究所小鼠和Sprague-Dawley（SD）大鼠，在注射BoNT/A后32周测量CMAP和DAS水平。我们使用虚拟药代动力学（PK）隔室结合间接反应模型开发了一个肌肉收缩抑制模型，并使用拟合优度分析、视觉预测检查（VPC）和自助法分析进行模型诊断。CMAP和DAS曲线呈剂量依赖性，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，并提供了关于PK和PD参数物种特异性差异的见解。总体而言，本研究证明了PK-PD建模在理解BoNT/A作用方面的实用性，并为未来其他BoNT/A产品的研究奠定了基础。
