Camp. Biochem. Physiol. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Vol. 103C, No. 2, pp. 249-253, 1992 Printed in Great Britain 0306-4492/92 $5.00 + 0.00 Pergamon Press Ltd zyxwvutsrqp MINI-REVIEW THE ALLOMETRIC APPROACH FOR INTERSPECIES SCALING OF PHARMACOKINETIC PARAMETERS W. A. RITSCHEL,* N. N. VACHHARAJANI, R. D. JOHNSON and A. S. HUSSAIN Division of Pharmaceutics and Drug Delivery Systems, College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, OH 45267-004, U.S.A. (Tel. 513-558-0726; Fax. 513-558-4372) (Received 16 March 1992; accepted for publication 15 April 1992) INTRODUCTION The drug development process for the marketing of new drugs in the U.S. is a time consuming and expensive process. Ethical constraints require the pharmacokinetic characterization of new drugs to be performed in at least two different animal species prior to testing in humans (Gogerty, 1987). However, in most cases, the pharmacokinetics of drugs in animals differs from that in humans. Thus, to make animal experimentation meaningful, a need exists to scale or extrapolate the distribution and elimination characteristics of new drugs from one species to another and ultimately to that in man (Mordenti, 1986). Interspecies scaling (IS) in pharmacokinetics may be accomplished through the application of physio- logically based models or by an empirical allometric procedure. Both methods have their advantages and disadvantages. Physiological models, which offer a mechanistic evaluation of the drug distribution and elimination processes, utilize organ blood flow rates, organ size, tissue to blood partitioning, and meta- bolic chemical reaction rates to write a series of coupled first-order differential equations to depict the concentration of drug in blood and the various organs as a function of time. The tissue to blood partitioning and the metabolic chemical reaction rates are determined in an animal species of choice (usually the rat because of ease in experimentation). The concentration-time profile in man is then simu- lated by numerically solving the system of differential equations assuming tissue binding and metabolic equivalency between man and animal along with the appropriate blood flow and organ size parameters of man (Ings, 1990). There are several examples where this procedure has been applied and used as a predic- tive tool (Benowitz et al., 1974a,b; Bischoff, 1975; Himmelstein and Lutz, 1979; Sugita et al., 1982; Boddy et al., 1989). Despite the fact that these models provide an inherent understanding of drug disposi- tion, physiologic models have found only limited use because of their complexity, cost, and time- *Author to whom correspondence should be addressed. involvement with frequent failures of initial models resulting in restructuring and reparameterization to give good predictions. The allometric approach, although entirely empiri- cal, is easy to apply and does not require a sophisti- cated mathematical background. This approach attempts to establish a quantitative relationship be- tween the different pharmacokinetic parameters and the physical characteristics of the various animal species such as body weight, liver weight, brain weight, body surface area, and maximum life span potential. This review focuses on the basic principles and application of the allometric scaling technique in pharmacokinetics. INTERSPECIES SCALING: PAST AND PRESENT It has been recognized for many years that, although there are definite differences in outward appearance among the various mammalian species, all mammals are quite similar with regard to basic physiology and physiological processes. As early as 1637, Galileo discussed the relationship between skel- etal size and total body mass (cited in Boxenbaum, 1982). Adolph (1949), however, was the first to recognize the quantitative relationship between body weight and many basic biological parameters of mammals. However, this approach was first used by Weiss and coworkers (1977) to scale the pharmacoki- netic parameters among various species. A historical perspective of IS in pharmacokinetics is given in Table 1. IS was initially used in the early 1970s and 1980s as a tool in the development of anticancer drugs. As mentioned earlier, current FDA guidelines require pharmacokinetics of a new substance to be determined in at least two different species. But to apply IS, pharmacokinetic evaluation in at least three to four different species is required. Thus, due to such limitations and time-involvement the interest in IS declined. However, the recent epidemic of AIDS, and increasing awareness towards environ- mental carcinogens has once again rejuvenated the interest to find the common denominator among 249