Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, S100, Salt Lake City, UT, 84108, USA.
Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
Clin Pharmacokinet. 2019 Jan;58(1):1-13. doi: 10.1007/s40262-018-0677-y.
Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug-drug interactions, real-time assessment of pharmacokinetic-safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokinetic modeling strategies and approaches in pediatrics. We discuss the impact of physiologically based pharmacokinetic models on regulatory reviews and product labels in the field of pediatric pharmacotherapy. Additionally, we examine in detail the current limitations and future directions of physiologically based pharmacokinetic modeling in pediatrics with regard to the ability to predict plasma concentrations and pharmacokinetic parameters. Despite the skepticism and concern in the pediatric community about the reliability of physiologically based pharmacokinetic models, there is substantial evidence that pediatric physiologically based pharmacokinetic models have been used successfully to predict differences in pharmacokinetics between adults and children for several drugs. It is obvious that the use of physiologically based pharmacokinetic modeling to support various stages of pediatric drug development is highly attractive and will rapidly increase, provided the robustness and reliability of these techniques are well established.
基于生理学的药代动力学建模和模拟是预测儿科药物药代动力学、药效学和安全性的重要工具。基于生理学的药代动力学建模在儿科药物开发中得到了应用，包括首次在儿科中的剂量选择、基于模拟的试验设计、与靶器官毒性的相关性、通过研究潜在的药物相互作用进行风险评估、实时评估药代动力学-安全性关系，以及评估非系统性生物分布目标。本文综述了儿科药物研究中基于生理学的药代动力学建模方法的细节，强调了个体药物的儿科基于生理学的药代动力学模型的报告。我们还比较和对比了不同研究人员在儿科基于生理学的药代动力学建模中采用的策略，并提供了儿科基于生理学的药代动力学建模策略和方法的全面概述。我们讨论了基于生理学的药代动力学模型对儿科药物治疗领域监管审查和产品标签的影响。此外，我们详细研究了儿科基于生理学的药代动力学建模在预测血浆浓度和药代动力学参数方面的当前限制和未来方向。尽管儿科领域对基于生理学的药代动力学模型的可靠性存在怀疑和担忧，但有大量证据表明，儿科基于生理学的药代动力学模型已成功用于预测几种药物在成人和儿童之间的药代动力学差异。显然，基于生理学的药代动力学建模用于支持儿科药物开发的各个阶段具有很高的吸引力，并将迅速增加，前提是这些技术的稳健性和可靠性得到很好的确立。
