A Practical Approach, Second Edition=Ronald D. Ho.pdf

274 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONhave started to address the need to evaluate drugs for children in a similar manner as they are foradults.2. Predictive ValueThe traditional model for prediction of potential hazards in pediatric patients is to consider studydata (safety, effectiveness, and exposure) from previous adult human studies, as well as data fromnonclinical repeated-dose toxicity, reproductive toxicity, and genotoxicity studies. 48 However, thismodel inherently assumes (correctly or incorrectly) that a similar disease progression occursbetween children and adults, that there will be a comparable response to the drug for a specificindication, and that there are no differences between adults and developing children that may affectthe safety profile. Therefore, given that there are known differences between pediatric and adultpatients that can affect risk-benefit analysis, and that acceptable concordance has been shown forthe predictability of drug toxicity between adult animals and humans, nonclinical juvenile studiesshould be used to predict potentially adverse events prior to the initiation of pediatric clinicaltrials. 50,76In general, some juvenile animals (e.g., rodents, dogs, minipigs, nonhuman primates) exhibitage-related and developmental characteristics similar to those in the human pediatric population,thus making them suitable for toxicity testing. 77 Because of these similarities, nonclinical juvenilestudies have been shown to be useful for identifying, evaluating, or predicting age-related toxicitiesin children. For example, the adverse effects of phenobarbital on cognitive performance in childrenare predicted by administration of the drug to the developing rodent during periods of criticalneurodevelopment. 78,79 Increased sensitivity of human infants to hexachlorophene neurotoxicity wasreplicated and evaluated in juvenile rats of comparable developmental age. 80 Proconvulsant effectsobserved in developing rodents treated with theophylline could be predictive of risk to similareffects in children. 81 In addition, a juvenile rat model has been used to understand the toxic effectson craniofacial growth and development observed in young children administered prophylactictreatments (irradiation with or without chemotherapeutic drugs) to reduce the recurrence of childhoodacute lymphoblastic leukemia. 4 Unfortunately, most of these examples of the predictive utilityof nonclinical juvenile studies for identifying adverse events occurred after the adverse events wereidentified in children.III. DESIGN CONSIDERATIONSFOR NONCLINICAL JUVENILE TOXICITY STUDIESWhen designing nonclinical juvenile toxicity studies, various factors must be considered to obtaindata that allow the assessment of the toxicological profile of a compound in young animals andprovide information pertaining to specific endpoints deemed important based on existing clinicaland/or nonclinical data. For example, the intended use of a drug and the intended target populationmust be addressed, along with the developmental period of exposure in the target population. Theduration of clinical use of a drug must also be considered when determining the proper exposureperiod in animal studies. The test article exposure regimen in an animal model should correspondto the intended exposure period in the human target population. Finally, to the extent possible,inter- and intraspecies physiological, pharmacological, and toxicological profiles should be understood.A. Intended or Likely Use of Drug and Target PopulationJuvenile toxicity studies are often conducted in the rat, which is a species that reaches adult statusmuch more rapidly than humans (as illustrated in Figure 8.2). This compression of physiological© 2006 by Taylor & Francis Group, LLC