Allometric scaling of pharmacokinetic parameters in drug discovery:: Can human CL, VSS and t1/2 be predicted from in-vivo rat data?

In a drug discovery environment, reasonable go/no-go human in-vivo pharmacokinetic (PK) decisions must be made in a timely manner with a minimum amount of animal in-vivo or in-vitro data. We have investigated the accuracy of the in-vivo correlation between rat and human for the prediction of the total systemic clearance (CL), the volume of distribution at steady state (V,,), and the half-life (t(1/2)) using simple allometric scaling techniques. We have shown, using a large diverse set of drugs, that a fixed exponent allometric scaling approach can be used to predict human in-vivo PK parameters CL, V-ss and t(1/2) solely from rat in-vivo PK data with acceptable accuracy for making go/no-go decisions in drug discovery. Human in-vivo PK predictions can be obtained using the simple allometric scaling relationships CLHuman approximate to 40 CL (Rat) (L/hr), V-ss (Human) approximate to 200 V-ss Rat (L), and t(1/2 Human) approximate to 4 t(1/2) (Rat) (hr). The average fold error for human CL predictions for N = 176 drugs was 2.25 with 79% of the drugs having a fold error less than 3. The average fold error for human V-ss predictions for N = 144 drugs was 1.85 with 84% of the drugs having a fold error less than 3. The average fold error for human t(1/2) predictions for N = 145 drugs was 2.05 with 76% of the drugs having a fold error less than 3. Using these simple allometric relationships, the sorting of drug candidates into a low/medium/high/very high human classification scheme was also possible from rat data. Since these simple allometric relationships between rat and human CL, V-ss, and t(1/2) are reasonably accurate, easy to remember and simple to calculate, these equations should be useful for making early go/no-go ill-vivo human PK decisions for drug discovery candidates.