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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants
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Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

机译：在早产儿的单克隆抗体的生理基于基于生理学药代理模型的整合

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Abstract An understanding of pediatric pharmacokinetics (PK) is essential for first‐in‐pediatric dose selection and clinical trial design. At present, there is no reliable way to scale the PK of monoclonal antibodies and immunoglobulin G drug products from adults to young children or to premature infants—a vulnerable population with a rapidly growing drug development pipeline. In this work, pediatric physiologically based PK models are constructed in PK‐Sim and Mobi to explore the PK of pagibaximab, palivizumab, MEDI8897, and intravenous immunoglobulin in preterm infants. In addition to considering ontogeny in pediatric organ volumes, organ composition, blood flow rates, and hematocrit, advanced ontogeny is applied for 3 key parameters: capillary surface area, hematopoietic cell concentration, and lymph flow rate. The role and importance of each parameter for determining pediatric clearance (CL) and volume of distribution at steady state (V SS ) are quantitatively assessed with a local sensitivity analysis. In addition, the uncertainty around parameters with limited information in pediatrics is addressed (eg, free neonatal Fc receptor concentration). The full ontogeny parameterization yields pediatric PK predictions that are within 1.5‐fold prediction error 90% of the time for preterm infants, with an absolute average fold error of 1.05. This result suggests that many of the key factors related to ontogeny are appropriately addressed. Overall, this study makes a first step toward developing a platform pediatric physiologically based PK model for monoclonal antibodies and immunoglobulin G drug products by solidifying existing parameterizations, integrating new concepts, and drawing attention to unmet needs for physiologic knowledge in children.
机译：摘要对儿科药代动力学（PK）的理解对于先小儿科剂量选择和临床试验设计至关重要。目前，没有可靠的方法可以将单克隆抗体和免疫球蛋白G药物产品从成人到幼儿或过早的婴儿 - 一种脆弱的人群，脆弱的药物开发管道。在这项工作中，小儿生理学基础的PK模型是在PK-SIM和Mobi构建的，探索Pagibaximab，Palivizumab，Medi8897和静脉内免疫球蛋白的早产儿。除了考虑儿科器官体积，器官组合物，血流率和血细胞比容外，还施加先进的组成，涂布3个关键参数：毛细管表面积，造血细胞浓度和淋巴流速。通过局部敏感性分析定量评估每种参数用于确定小儿间隙（CL）和稳态（V SS）的分布的作用和重要性。此外，解决了儿科信息有限的参数周围的不确定性（例如，自由新生儿Fc受体浓度）。全组织化参数化产生的儿科PK预测在1.5倍的预测误差范围内。90％的早产婴儿的时间，绝对平均折叠误差为1.05。该结果表明，适当地解决了与组织发生相关的许多关键因素。总体而言，这项研究通过巩固现有的参数化，整合新概念，对儿童的生理知识的未满足需求来开发单克隆抗体和免疫球蛋白G药品进行单克隆抗体和免疫球蛋白G药物产品的平台小儿生理学基于PK模型。

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