Interspecies scaling: Predicting volumes, mean residence time and elimination half-life. Some suggestions

Extrapolation of animal data to assess pharmacokinetic parameters in man is an important tool in drug development. Clearance, volume of distribution a nd elimination half-life are the three most frequently extrapolated pharmac okinetic parameters. Extensive work has been done to improve the predictive performance of allometric scaling for clearance. In general there is good correlation between body weight and volume, hence volume in man can be pred icted with reasonable accuracy from animal data. Besides the volume of dist ribution in the central compartment (V-c), two other volume terms, the volu me of distribution by area (V-beta) and the volume of distribution at stead y state (Vd(ss)), are also extrapolated from animals to man. This report co mpares the predictive performance of allometric scaling for V-c, V-beta and Vd(ss) in man from animal data. The relationship between elimination half-life (t1/2) and body weight acros s species results in poor correlation, most probably because of the hybrid nature of this parameter. To predict half-life in man from animal data, an indirect method (CL=VK, where CL=clearance, V is volume and K is eliminatio n rate constant) has been proposed. This report proposes another indirect m ethod which uses the mean residence time (MRT). After establishing that MRT can be predicted across species, it was used to predict half-life using th e equation MRT = 1.44 x t1/2. The results of the study indicate that V, is predicted more accurately than Vp and Vdss in man. It should be emphasized that for first-time dosing in man, V,is a more important pharmacokinetic parameter than Vp or Vdss. Furth ermore, MRT can be predicted reasonably well for man and can be used for pr ediction of half-life.