Use of Pharmacokinetic Data Under the FDA's Redbook II Guidelines for Direct Food Additives

Abstract

Experience with food additive petitions submited after publication of the Food and Drug Administration's Redbook I (U. S. FDA, 1982) guide lines indicated a number of areas in which improvements were needed, and advances in toxicol-ogy testing during the last decade required additional rev is ions. In March 1993, the FDA's Center for Food Safety and Applied Nutrition (CFSAN) distributed copies of a draft of Redbook II for public comment. Since that time, revisions have been made based on comments received on the initial draft. This article describes the rationale for Redbook II guidance on the design of pharm acoki-netic studies and discusses some common problems the FDA has encountered in reviewing pharmacokine tic data submitted as part of food additive petitions. Points emphasized are that (1) pharmaco kinetic information is needed for the interpretation of toxicity studies and is most use ful when conducted before major toxicity studies, (2) the use of whole-body autoradiography is encouraged as a means to select tissues of interest, and as a substitute for dissection and tis-sue sampling, (3) kinetic and mechanistic studies conducted with blood compo-nents, tissue slices, hepatocytes, and othercell types in vitro ofien provide more useful information on the fate of chemicals in specific tissues than information extracted from whole-animal studies. The intention of th e new guide lines for pharmaco kinetic studies is to increase the information content of data gathered and to encourage the use of pharmaco kinetic models and results in the selection of doses for subchronic, chronic, and developmental toxicity studies.