Serial allometric factor extrapolation: compartmental and physiological pharmacokinetic approaches.
Interspecies dose-response equivalence is most frequently estimated as the product of a reference species dose and a single scaling ratio based on a physiological parameter such as body weight, body surface area, maximum lifespan potential, DNA repair rate, etc. This approach may suffice for certain narrowly defined applications but is likely to be inadequate or inappropriate for many others. A biologically plausible rationale for these inadequacies and for their resolution can be demonstrated using a structured approach to dose scaling, termed serial allometric factor extrapolation (SAFE). The SAFE procedure is unique in that variations in chemical-specific toxic interaction mechanisms can be incorporated into the scaling process. The compartmental and physiological pharmacokinetic (PPK) bases for the procedure are demonstrated using published data on acute intravenous toxicity of chemotherapeutic agents in animals and humans. The interrelationships of SAFE equations, PPK, and regression allometry of dose response are discussed.
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Universities Associated for Research and Education in Pathology, Inc., Bethesda, MD 20814.
Wands
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D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000633:toxicity; D006224:Cricetinae; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D006801:Humans; D051379:Mice; D051381:Rats; D012044:Regression Analysis; D013045:Species Specificity
D000970:Antineoplastic Agents