Phase I Clinical Trial Center, Beijing Shijitan Hospital of Capital Medical University, Beijing, PR China (H.B., Xin.W.); State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, PR China (M.Y., J.C.); and Chinese Pharmaceutical Association, Beijing, PR China (Xia.W.).
Phase I Clinical Trial Center, Beijing Shijitan Hospital of Capital Medical University, Beijing, PR China (H.B., Xin.W.); State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, PR China (M.Y., J.C.); and Chinese Pharmaceutical Association, Beijing, PR China (Xia.W.)
Drug Metab Dispos. 2019 Nov;47(11):1361-1367. doi: 10.1124/dmd.119.086249. Epub 2019 Jul 19.
As a prominent human therapeutic, therapeutic monoclonal antibodies (mAbs) have attracted increasing attention in the past decade due to their high-targeting specificity, low toxicity, and prolonged efficacy. Systematic pharmacokinetic analysis of mAbs not only largely facilitates the understanding of their biologic functions but also promotes the development of therapeutic drug discovery, early clinical trial implementation, and therapeutic monitoring. However, the extremely complex nature of biomatrices and the especially low dosages of mAbs make their detection in biomatrices and further pharmacokinetic analysis highly challenging. Therefore, a method capable of reliably, quickly, and sensitively quantifying mAbs in biomatrices is urgently needed. In this work, we developed and evaluated an gold nanoparticle-functionalized surface plasmon resonance assay for cetuximab (C225) detection and pharmacokinetic analysis in rhesus monkeys. Combining its advantages of label-free pretreatment and amplified signal response, the lower limit of quantitation of C225 in monkey serum was reduced to 0.0125 g/ml, and the linear range had an order of magnitude comparable to that of an ELISA-based method. Furthermore, the pharmacokinetics of C225 in rhesus monkeys was studied after intravenous infusions of single doses at 7.5, 24, and 75 mg/kg. The concentration of C225 in monkey serum was detectable after dosing for 720 hours. We believe that this new strategy will be applicable as a general protocol for mAb quantification, pharmacokinetic characteristic determination, and toxicokinetic analysis during drug development.
作为一种重要的人类治疗药物，治疗性单克隆抗体（mAbs）因其高靶向特异性、低毒性和长效性，在过去十年中受到了越来越多的关注。mAbs 的系统药代动力学分析不仅极大地促进了对其生物学功能的理解，还推动了治疗药物发现、早期临床试验实施和治疗监测的发展。然而，生物基质的极其复杂性质和 mAbs 的特别低剂量使得它们在生物基质中的检测和进一步的药代动力学分析极具挑战性。因此，迫切需要一种能够可靠、快速和灵敏地定量生物基质中 mAbs 的方法。在这项工作中，我们开发并评估了一种基于金纳米粒子功能化表面等离子体共振（SPR）的方法，用于检测和分析猕猴体内西妥昔单抗（C225）的药代动力学。该方法结合了无标记预处理和信号放大的优势，将 C225 在猴血清中的定量下限降低到 0.0125 g/ml，线性范围与 ELISA 方法相当。此外，还研究了猕猴静脉注射单剂量 7.5、24 和 75 mg/kg 后 C225 的药代动力学。在 720 小时的给药后，可检测到 C225 在猴血清中的浓度。我们相信，这项新策略将适用于 mAb 定量、药代动力学特征确定以及药物开发过程中的毒代动力学分析的一般方案。
