THE ALLOMETRIC APPROACH FOR INTERSPECIES SCALING OF PHARMACOKINETICS AND TOXICITY OF ANTICANCER DRUGS

1. The rationale for extrapolation or 'scaling' across animal species is based on their underlying anatomical, physiological and biochemical similarities. 2. Research carried out in the 19th and early 20th cent ury resulted in Benedict's famous 'mouse-to-elephant' graph which show ed that the log of the basal metabolic rate plotted against the log of bodyweight (W) produced a straight line with a slope of 0.76. Since t hen it has become apparent that a number of other physiological variab les (Y) exhibit a similar relationship which can be represented by the general allometric equation, Y = W-alpha(beta); where beta is the slo pe of the log-log plot and alpha is the intercept on the y axis. 3. Th e major pharmacokinetic parameters such as clearance and volume of dis tribution of many drugs are also related to W in a similar manner. 4. This empirical approach does not require a strong mathematical backgro und and offers a relatively simple method of predicting the kinetics o f anti-cancer drugs in patients from pre-clinical animal data. 5. The occurrence of major qualitative and quantitative differences in the me tabolism of drugs between species is probably the single greatest comp licating factor in the use of animals as predictors of drug toxicity a nd kinetics in patients. 6. Despite this, the allometric approach is u seful for allowing the estimation of a more appropriate starting dose for some drugs in a Phase I trial, which might result in potential sav ings in escalation steps and maximize the chance that the dose which a n individual receives has the potential for therapeutic value.