Elzagallaai Abdelbaset A, Rieder Michael J
Department of Paediatrics, London, ON, Canada.
Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Front Pharmacol. 2021 Apr 30;12:638881. doi: 10.3389/fphar.2021.638881. eCollection 2021.
Drug use in children is-in most cases-supported by extrapolation of data generated from clinical trials in adult populations. This puts children at higher risk of developing adverse drug reactions (ADRs) due to "off-label" use of drugs and dosing issues. Major types of ADRs are drug hypersensitivity reactions, an idiosyncratic type of ADRs that are largely unpredictable and can cause high morbidity and mortality in a hard-to-identify specific population of patients. Lack of a complete understanding of the pathophysiology of DHRs and their unpredictive nature make them problematic in clinical practice and in drug development. In addition, ethical and legal obstacles hinder conducting large clinical trials in children, which in turn make children a "therapeutic orphan" where clear clinical guidelines are lacking, and practice is based largely on the personal experience of the clinician, hence making modeling desirable. This brief review summarizes the current knowledge of model-based evaluation of diagnosis and management of drug hypersensitivity reactions (DHRs) to antimicrobial drugs in the pediatric population. Ethical and legal aspects of drug research in children and the effect of different stages of child development and other factors on the risk of DHRs are discussed. The role of animal models, models and oral provocation test in management of DHRs are examined in the context of the current understanding of the pathophysiology of DHRs. Finally, recent changes in drug development legislations have been put forward to encourage drug developers to conduct trials in children clearly indicate the urgent need for evidence to support drug safety in children and for modeling to guide these clinical trials.
在大多数情况下，儿童用药是通过对成人临床试验数据的外推来支持的。这使儿童因药物的“超说明书”使用和给药问题而面临更高的发生药物不良反应（ADR）的风险。ADR的主要类型是药物超敏反应，这是一种特殊类型的ADR，在很大程度上不可预测，并且可能在难以识别的特定患者群体中导致高发病率和死亡率。对药物超敏反应（DHR）的病理生理学缺乏全面了解及其不可预测性，使得它们在临床实践和药物开发中成为难题。此外，伦理和法律障碍阻碍了在儿童中进行大型临床试验，这反过来又使儿童成为“治疗孤儿”，缺乏明确的临床指南，实践很大程度上基于临床医生的个人经验，因此使得建模成为必要。本简要综述总结了目前基于模型评估儿科人群对抗菌药物的药物超敏反应（DHR）的诊断和管理的知识。讨论了儿童药物研究的伦理和法律方面以及儿童发育的不同阶段和其他因素对DHR风险的影响。在当前对DHR病理生理学理解的背景下，研究了动物模型、模型和口服激发试验在DHR管理中的作用。最后，提出了药物开发立法的近期变化，以鼓励药物开发者在儿童中进行试验，这清楚地表明迫切需要证据来支持儿童用药安全以及需要建模来指导这些临床试验。
