Abstract
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, in vitro 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.
Highlights
An adverse drug reaction (ADR) is defined as any noxious and unintended response to a drug, which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease or modification of physiological function
Major maturation of body systems occur during the first few years of life and body water and fat compositions changes dramatically (Kauffman, 2019). All these factors put children at risk of developing ADRs as typically drugs are not studied in children during the process of drug development and approval and, safety data in this age group is almost always missing
Current clinical practice include detailed review of medical history; identifying the culprit drug may be complicated by polypharmacy
Summary
An adverse drug reaction (ADR) is defined as any noxious and unintended response to a drug, which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease or modification of physiological function. Understanding DHRs pathophysiology is crucial to the development and interpretation of in vitro tests for drug hypersensitivity as discussed further below. The main limitation of the test is possibility of provoking a full reaction, which makes it contraindicated in cases of severe life-threatening DHRs. it is only performed if other in vitro tests are negative or cannot confirm diagnosis (Figure 2).
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