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

290 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONOther routes of administration that are less commonly employed in nonclinical juvenile studiesare subcutaneous, intramuscular, and intraperitoneal injection. These routes are adaptable to thejuvenile animal, depending upon the age and species of the model.2. Frequency and Duration of ExposureThe frequency of dose administration prior to weaning will most often be once daily, with dosagesbased on daily body weight determination. Previous studies in adult animals, which may includekinetic information, will aid in developing the most appropriate regimen for the test article. However,the researcher is cautioned not to overlook differences in absorption, distribution, metabolism, andelimination (ADME) profiles between juvenile and adult animals, such as differences in the concentrationand/or activity of key metabolic pathways. Carefully designed pharmacokinetic studiesin juvenile rodents have revealed marked differences in clearance rates, peak plasma concentrations,and area under the curve (AUC) values for test articles when administered at different ages in thesame model. 92 These differences clearly demonstrate that developmental changes occurring inmetabolic pathways may result in significant quantitative differences in systemic exposure andinfluence the selection of exposure frequency.In addition, the treatment period must be considered when juvenile toxicity studies are designed.Consideration should be given to covering the entire period of growth, from the neonate to thesexually mature animal. In rodent models, test article administration from weaning until or beyondthe age when mating would occur may be required. Alternatively, administration may begin atapproximately PND 4 to 7, which is roughly equivalent to a preterm human infant, and continueuntil just after the males enter puberty, at approximately 6 to 7 weeks of age. At a minimum, thistreatment period, coupled with the adult general and reproductive toxicity studies that are alreadyrequired, would encompass all periods of the animal’s life span. If there is concern that a test articlemay reveal oncogenic potential as a result of juvenile (or even prenatal) exposure, a subset of animalsfrom a pre- and postnatal development study may be selected to become part of a carcinogenicity study,with dose administration beginning immediately following weaning. Dose administration throughoutgrowth may be impractical in large animal species (longer duration and higher cost), for which theentire growth and development period may span several months to years. At a minimum, in situationswhere a large animal model is the species of choice, the period of dose administration for a generalscreening study should cover the period of target organ system development (if known).A recovery (or posttreatment) period may be included in the design of the study. For some testarticles, changes in functional parameters are expected because of the pharmacological action.Therefore, there may be less concern regarding acute effects of the test article (e.g., locomotoractivity changes immediately following administration of a sedative) and more concern aboutwithdrawal, persistent, and/or latent effects. In addition, when the posttreatment period containsthe same assessments as those in the treatment period, comparisons can be made regarding theseverity of the changes, persistence of these changes, and their relationship to the expected pharmacologyof the test article. If functional assessments are not included in the treatment period,interpretation of findings during the posttreatment period becomes much more difficult. In thisscenario, responses in the juvenile study must be compared with those that may have been observedin studies with adult animals.3. Dose SelectionFor the general toxicity screen, the draft FDA guidance document recommends that the high doseproduce frank toxicity and that a no-observed-adverse-effect level be identified, if possible. 51However, when enzymatic pathways involved in metabolism of the test article are immature,different sensitivities may be observed between the adult and the juvenile. Moreover, functionalchanges in developing organ systems can create periods of greater sensitivity in the juvenile, with© 2006 by Taylor & Francis Group, LLC