The pharmacokinetic principles behind scaling from preclinical results to phase I protocols

Extrapolation of animal data to assess pharmacokinetic parameters in humans is an important tool in drug development. Allometric scaling has many prop onents, and many different approaches and techniques have been proposed to optimise the prediction of pharmacokinetic parameters from animals to human s. The allometric approach is based on the power function Y = aW(b), where the bodyweight of the species is plotted against the pharmacokinetic parame ter of interest on a log-logs scale. Clearance, volume of distribution and elimination half-life are the 3 most frequently extrapolated pharmacokineti c parameters. Clearance is not predicted very well terror between predicted and observed clearance >30%) using the basic allometric equation in most cases. Thus, se veral other approaches have been proposed. An early approach was the concep t of neoteny, where the clearance is predicted on the basis of species body weight and maximum life-span potential. A second approach uses a 2-term pow er equation based on brain and bodyweight to predict the intrinsic clearanc e of drugs that are primarily eliminated by phase I oxidative metabolism. M ost recently, the use of the product of brain weight and clearance has been proposed. A literature review reveals different degrees of success of impr oved prediction with the different methods for various drugs. In a comparat ive study, the determining factor in selecting a method for prediction of c learance was found to be the value of the exponent. Integration of in vitro data into in vivo clearance to improve the predictive performance of clear ance has also been suggested. Although there are proponents of using body s urface area instead of bodyweight, no advantage has been noted in this appr oach. It has also been noted that the unbound clearance of a drug cannot be predicted any better than the total body clearance (CL). In general, there is a good correlation between bodyweight and volume of th e central compartment (V-c); hence, V-c does not face the same complication s as CL. The relationship between elimination half-life (t1/2 beta) and bodyweight a cross species results in poor correlation, most probably because of the hyb rid nature of this parameter. When a reasonable prediction of CL and V-c is made, t1/2 beta may be predicted from the equation t1/2 beta = 0.693V(c)/C L.