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

NONCLINICAL JUVENILE TOXICITY TESTING 291resulting toxicities that would not be evident in the adult. Therefore, dose levels used for adultanimals may not be applicable to juvenile animals. As an example, the benzodiazepines produceparadoxical responses in opposition to their anxiolytic properties, including convulsions. 112 Thoseconvulsions were characterized in preweaning rats and were postulated to result from differencesin the Type 1 and Type 2 benzodiazepine receptor sites expressed in immature and mature rats.Another example of apparent differential sensitivity between adults and juveniles relating toenzyme system competence is that of the pyrethroids. 113 As an example, the LD 50 for cypermethrin(a type II pyrethroid) is far lower in juvenile rats than in adults of the same strain. However, whentri-o-tolyl phosphate was used to inhibit drug metabolism prior to treatment in the adult to mimicthe inherently lower esterase level in the juvenile rat, the observed LD 50 at both developmentalstages became similar. 114 An interesting age-related manifestation of toxicity of a type II pyrethroidevaluated in the authors’ laboratory in the juvenile rat is a gait abnormality that was termed“carangiform ataxia.” This abnormality is a fish-tailing gait wherein the forepaws pedal in a forwarddirection while the posterior third of the body (behind the rib cage) rapidly oscillates in a fishlikemotion with maximal lateral abdominal flexion. Carangiform ataxia is temporally limited andgenerally corresponds to the time of locomotor function development in the rat during whichpivoting is observed (approximately PND 6 to 11). 115 This age-specific manifestation of pyrethroidtoxicity is speculated to result from the limited neural development in the hindquarters of the ratat this age; there is no known adult correlate. This gait abnormality was observed in juvenile ratsat a dose level approximately 10-fold lower than the dose level that produced maternal toxicity,emphasizing both the apparent sensitivity of juveniles and the possibility of unique manifestationsof toxicity based on physiological development. For current thinking and future directions in thestudy of developmental neurotoxicity of pyrethroid insecticides, the reader is referred to a recentreview article by Shafer et al. 116Dose selection in a general sense requires careful consideration of adult nonclinical data, datafrom analogs, existing human exposure data, and knowledge of the organ systems that are developingduring the proposed period of dose administration. In addition, well-designed range-findingstudies are essential for the selection of acceptable dose levels. In these studies, gross changes inbody weight, food consumption, and clinical chemistry, and macroscopic changes in organ structureand weight can be evaluated. Although less commonly included in dose range-finding studies inadult animals, pharmacokinetic profiling of the test article can be extremely valuable in the selectionof dose levels for the definitive juvenile study. The pharmacokinetic profile (e.g., C max , AUC) inthe juvenile after direct administration can be compared with previously developed profiles in adultanimals. Any potential differences that are identified can provide guidance as to the modificationsin the dosage levels, dosage regimen, vehicle, etc., that may be required. Moreover, to date manynonclinical juvenile studies are being conducted after some initial data have been developed in thehuman. In these circumstances, inclusion of a pharmacokinetic phase in the dose range-findingstudy will guide the researcher to select dose levels that will more accurately reflect the humanexposure scenario or that may even indicate the appropriateness of the species as a model for thehuman situation.As stated previously, the FDA draft guidance document recommends that the high dose shouldproduce frank toxicity. 51 One way to ensure that toxicity is observed is by reaching the maximumtolerated dose (MTD). Since clinical studies in the pediatric population will only characterize theefficacy of the drug, and perhaps some side effects, reaching an MTD in the nonclinical juvenilestudy will allow for an examination of the range of potential adverse outcomes following exposure.However, several challenges may be imposed by the use of the MTD. For example, reaching anMTD in an adult study will result in toxicity that may be limited to a single organ system.Conversely, administration of the test article to a juvenile animal population at a dose level at orabove the MTD may not only result in an adverse outcome in a particular organ or organ systembut may also result in confounding growth retardation. The authors have experience using doselevels that were far above the MTD for the juvenile. One example was a developmental neurotoxicity© 2006 by Taylor & Francis Group, LLC