DSTA4637A, a THIOMAB™ antibody-antibiotic conjugate targeting Staphylococcus aureus, has shown promising bactericidal activity in a mouse model. DSTA4637A consists of a monoclonal anti-S. aureus antibody with an average of two rifalogue antibiotic molecules, dmDNA31, linked to its light chains. The goal of this study was to develop a minimal physiologically-based pharmacokinetic (mPBPK) model to characterize the pharmacokinetic (PK) properties of three analytes of DSTA4637A (i.e., total antibody, antibody-conjugated dmDNA31, and unconjugated dmDNA31) in mice, and to predict pharmacokinetics of DSTA4637A analytes in humans, as well as to provide an initial assessment for potential PK drug-drug interactions (DDI) in clinical trials via cross-species scaling of the mPBPK model. In the proposed model, selected organs, including heart, liver, and kidney, were connected anatomically with plasma and lymph flows. Mouse plasma and tissue concentrations of the three analytes of DSTA4637A were fitted simultaneously to estimate the PK parameters. Cross-species scaling of the model was performed by integrating allometric scaling and human physiological parameters. The final mPBPK model was able to successfully capture PK profiles of three DSTA4637A analytes in mouse plasma and in investigated organs. The model predicted a steady-state peak unbound dmDNA31 concentration lower than 5% of the IC₅₀ of dmDNA31 towards cytochrome P450 following 100 mg/kg weekly intravenous dose, which suggests a low risk of PK DDI in humans for DSTA4637A with co-administered cytochrome P450 substrates. The proposed mPBPK modeling and cross-species scaling approaches provide valuable tools that facilitate the understanding and translation of DSTA4637A disposition from preclinical species to humans.

DSTA4637A是一种针对金黄色葡萄球菌的THIOMAB™抗体-抗生素共轭物，已在小鼠模型中显示出有希望的杀菌活性。DSTA4637A由单克隆抗金黄色葡萄球菌组成轻链中平均含有两个利福平抗生素分子dmDNA31的抗体。这项研究的目的是建立一个最小的基于生理的药代动力学（mPBPK）模型，以表征DSTA4637A三种分析物（即总抗体，抗体缀合的dmDNA31和未缀合的dmDNA31）的药代动力学（PK）特性，以及通过mPBPK模型的跨物种定标，预测DSTA4637A分析物在人体中的药代动力学，并为临床试验中潜在的PK药-药相互作用（DDI）提供初步评估。在提出的模型中，选定的器官，包括心脏，肝脏和肾脏，在解剖学上与血浆和淋巴流相连。同时拟合DSTA4637A三种分析物的小鼠血浆和组织浓度，以估计PK参数。该模型的跨物种缩放是通过整合异速缩放和人类生理参数来进行的。最终的mPBPK模型能够成功捕获小鼠血浆和研究器官中三种DSTA4637A分析物的PK谱。该模型预测稳态峰未结合的dmDNA31浓度低于IC的5％每周静脉给予100 mg / kg剂量后，有₅₀的dmDNA31趋向于细胞色素P450，这表明DSTA4637A与共同施用的细胞色素P450底物对人的PK DDI风险较低。拟议的mPBPK建模和跨物种缩放方法提供了有价值的工具，可促进对DSTA4637A处置从临床前物种到人类的理解和翻译。