Chae Soon Uk, Min Jee Sun, Jo Seong Jun, Lee Chae Bin, Park Jinha, Bae Soo Hyeon, Bae Soo Kyung
College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea.
Department of Pharmaceutical Sciences, State University of New York, Buffalo, NY 14214, USA.
Transl Clin Pharmacol. 2025 Mar;33(1):27-39. doi: 10.12793/tcp.2025.33.e4. Epub 2025 Mar 24.
Bee venom is a traditional remedy used to treat conditions related to the nervous and musculoskeletal systems, as well as autoimmune diseases. Recently, we developed a new composition bee venom (NCBV), a fortified content of bee venom phospholipase A2 (bvPLA2), which may be effective in the treatment of Alzheimer's disease. NCBV is currently preparing to conduct a phase 1 clinical trial, and this study aimed to predict the first-in-human (FIH) dose using a mechanistic approach. First, animal pharmacokinetic (PK) studies from three different species were explored and integrated to build a PK model using nonlinear mixed-effect modeling. The final models were described by two-compartment model with first order absorption and elimination, and were used to define the PK parameters for each species. To predict human PK parameters, simple, brain weight (BrW) or maximum lifespan potential (MLP) incorporated allometric scaling approaches were used, with the BrW method showing the highest correlation (R = 0.974). The initial FIH dose was back-calculated based on the area under the concentration-time curve of 0.397 μg·h/mL after the injection of an efficacious dose of 0.1 mg/kg in mice using the developed PK model. The predicted initial doses for a 70 kg human were 5.5, 1.3, and 3.5 mg, when using the simple, BrW, and MLP incorporated model, respectively. A subcutaneous FIH dose of 1.3 mg NCBV was ultimately recommended for a 70-kg human. Based on the no observed adverse effect level, the suggested FIH dose ranges for NCBV are 0.1 to 3 mg, which correspond with our proposed dose.
蜂毒是一种传统疗法，用于治疗与神经和肌肉骨骼系统相关的病症以及自身免疫性疾病。最近，我们开发了一种新型蜂毒组合物（NCBV），其富含蜂毒磷脂酶A2（bvPLA2），可能对治疗阿尔茨海默病有效。NCBV目前正准备进行1期临床试验，本研究旨在使用机制方法预测首次人体（FIH）剂量。首先，探索并整合了来自三个不同物种的动物药代动力学（PK）研究，以使用非线性混合效应建模构建PK模型。最终模型由具有一级吸收和消除的二室模型描述，并用于定义每个物种的PK参数。为了预测人体PK参数，使用了简单的、纳入脑重量（BrW）或最大寿命潜力（MLP）的异速生长缩放方法，其中BrW方法显示出最高的相关性（R = 0.974）。使用开发的PK模型，根据在小鼠中注射0.1 mg/kg有效剂量后浓度-时间曲线下面积为0.397μg·h/mL反推初始FIH剂量。对于体重70 kg的人，使用简单模型、纳入BrW模型和纳入MLP模型时预测的初始剂量分别为5.5 mg、1.3 mg和3.5 mg。最终建议体重70 kg的人皮下注射1.3 mg NCBV作为FIH剂量。基于未观察到不良反应水平，NCBV建议的FIH剂量范围为0.1至3 mg，这与我们提出的剂量一致。
