Interspecies scaling and comparisons in drug development and toxicokinetics

Abstract

1. Methods of interspecies extrapolation using physiological models and allometric scaling have been reviewed with their possible application to drug development, both for candidate drug selection and the interpretation of toxicokinetic data. 2. Physiological models offer a mechanistic approach to extrapolation from one species to another, examining individual components which interrelate to produce the characteristics of the whole system. Tissues of interest are arranged in anatomical order based on blood circulation, and the disposition of a drug can be simulated with knowledge of tissue size (volume), tissue perfusion (blood flow), drug permeability, binding of the drug between the tissue and blood (partition), as well as elimination. Using this approach the behaviour of the drug under different conditions, such as dose route, disease state or animal species, can be predicted. 3. The alternative approach of allometric scaling is an empirical examination of relationships between size, time and its consequences. A regression of the logarithm of the pharmacokinetic parameter and the logarithm of the body weight of the animal species produces a linear relationship which enables the value of pharmacokinetic parameters in any animal species to be calculated from the product of an allometric coefficient and the body weight to a power function. 4. Whilst this technique gives acceptable predictions for the pharmacokinetics of those drugs eliminated renally, or which are blood flow-dependent, there is poor prediction for humans for low clearance drugs primarily eliminated by the mixed-function oxidase system. This appears to be a result of differences in maturation, and can be corrected for by including a brain weight or maximum life-span potential term into the allometric equation. 5. Of the two approaches described for extrapolation of pharmacokinetics between animal species, physiological models tend to be resource-demanding and costly, with more frequent failures, but can be invaluable for examining target organ exposure and for the targeting of drugs as in cancer chemotherapy. For routine drug development, however, allometric scaling is potentially more useful since it uses data which are routinely obtained and the calculations are relatively simple. 6. The problems of intraspecies scaling from high-dose data to low-dose predictions are discussed with respect to current models of dose levels. A new approach is proposed using a modified Hill equation based on drug exposure, which should allow for a more meaningful determination of the toxicity of a compound with different drug exposures.(ABSTRACT TRUNCATED AT 400 WORDS)

Preclinical pharmacokinetics, pharmacodynamics, and activity of a humanized anti‐CD40 antibody (SGN‐40) in rodents and non‐human primates

“…Treatment of the animals was in accordance with regulations outlined in the USDA Animal Welfare act and the conditions specified in The Guide for Care and Use of Laboratory Animals (Institute of Laboratory Animal Research, 1996).…”

“…In this equation, A is the coefficient (y-axis intercept), B is body weight, and a is the power function (slope) (Ings, 1990). Regression analysis showed that clearance is strongly correlated with body weight across species.…”

Pharmacokinetic Profile of Single and Repeated Oral Doses of MDMA in Squirrel Monkeys: Relationship to Lasting Effects on Brain Serotonin Neurons

“…For this experiment, four squirrel monkeys were used. Three of the four animals had participated in prior substituted amphetamine toxicity studies (Table 1); all other experiments reported in this Mordenti and Chappell, 1989;Ings, 1990;Boxenbaum and DiLea, 1995;Mahmood, 1999Mahmood, , 2002Mahmood et al, 2003). Each monkey was administered a dose calculated using their individual weight at the time of administration.…”

“…One difference appears to be that 'equivalent' single doses produce higher plasma concentrations of MDMA in the squirrel monkey than in the human. For example, the 7.4 mg/kg dose in the monkey, estimated to be comparable to a 2 mg/kg dose in a human by the allometric method (for discussion of the method, including its limitations, see Mordenti and Chappell, 1989;Ings, 1990;Boxenbaum and DiLea, 1995;Mahmood, 2002;Mahmood et al, 2003) produced a C max of 773 ng/ml (Figure 1), whereas the 'equivalent' dose in humans (150 mg given to two subjects weighing approximately 75 kg) produced a C max ranging from 442 to 487 ng/ml (de la Torre et al, 2000). The higher plasma MDMA concentration in squirrel monkeys than humans could reflect limits of sample size, limitations of interspecies dose scaling methods using an allometric equation, or effects of stress of our experimental procedures (Johnson et al, 2004).…”

Caveat Emptor Editors Beware

“…Allometric interspecies scaling is based on the fact that the regression of the logarithm of a pharmacokinetic parameter and the logarithm of species weight is generally linear. As a result, pharmacokinetic (and therefore pharmacodynamic, including toxicity) parameters for a given drug can be estimated in any species if this linear relationship is determined (Ings 1990). Yates and Kugler (1986) and others have criticized the potential inaccuracy of interspecies scaling, noting the 10-fold range of estimates that may be derived depending on which pharmacokinetic and corrective factors are thought relevant.…”