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

CHAPTER 8Nonclinical Juvenile Toxicity TestingMelissa J. Beck, Eric L. Padgett, Christopher J. Bowman,Daniel T. Wilson, Lewis E. Kaufman, Bennett J. Varsho,Donald G. Stump, Mark D. Nemec, and Joseph F. HolsonCONTENTSI. Introduction ........................................................................................................................264A. Objectives...................................................................................................................265B. Background................................................................................................................2651. Historical Perspective of Pediatric Therapeutics ................................................2662. Adverse Events ....................................................................................................2673. Agency Intervention/Regulatory Guidelines.......................................................267II. Importance of Juvenile Animal Studies.............................................................................272A. Differences in Drug Toxicity Profiles between Developing andDeveloped Systems....................................................................................................272B. Utility of Studies in Juvenile Animals......................................................................2731. Clinical Considerations........................................................................................273III.2. Predictive Value ...................................................................................................274Design Considerations for Nonclinical Juvenile Toxicity Studies....................................274A. Intended or Likely Use of Drug and Target Population...........................................274B. Timing of Exposure in Relation to Phases of Growth and Developmentof Target Population ..................................................................................................275C. Potential Differences in Pharmacological and Toxicological Profilesbetween Mature and Immature Systems...................................................................276D. Use of Extant Data ....................................................................................................2771. Pharmacokinetic (PK) and Toxicokinetic (TK) Data in Adult Animals ............2772. Extant Adult Nonclinical Animal Toxicity Data.................................................2803. Stand-Alone Juvenile PK and TK Studies..........................................................280IV. Juvenile Toxicity Study Design .........................................................................................280A. Types of Studies ........................................................................................................2801. General Toxicity Screen ......................................................................................2812. Adapted Adult Toxicity Study.............................................................................2813. Mode of Action Study .........................................................................................283263© 2006 by Taylor & Francis Group, LLC