Interspecies Conversion of Kinetically Equivalent Doses

A framework is presented within which to organize consideration of appropriate measures of delivered dose and selection of an appropriate procedure for interspecies conversion of kinetically equivalent doses. Systematic species dependencies of simple kinetic relationships between administered and delivered dose are developed. Interspecies scaling of kinetic parameters, including firstorder rate constants and maximum rates of capacity‐limited processes, is discussed, and the effects of conventional scaling procedures on initial and steady‐state concentrations and on areas under the blood concentration curve are shown. Particular attention is given to production of reactive metabolites. It is shown that interspecies dose or dose rate conversion on the basis of the 3/4 power of body weight is consistently either realistic or conservative when the conversion is carried out from smaller to larger species, except when first‐order elimination and capacity‐limited production of an active metabolite coexist. In this case, the 3/4 power of body weight conversion procedure may be either overpredictive or underpredictive, depending on the relative dependence of the efficiency of metabolite production and elimination on species body weight. Interspecies dose conversion on a direct mg/kg body weight basis is consistently much less conservative than the 3/4 power of body weight procedure, resulting when scaling from smaller to larger species in underestimation of delivered dose or of steady‐state concentration of both parent and metabolite for all of the kinetic relationships considered. Applicability and limitations of these procedures are also discussed.