Allometric scaling of pharmacokinetic parameters in drug discovery: Can human CL, V ss and t 1/2 be predicted from in-vivo rat data?

Summary 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 ss ), 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 CL Human ≈ 40 CL Rat (L/hr), V ss Human ≈ 200 V ss Rat (L), and t 1/2 Human ≈ 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 in-vivo human PK decisions for drug discovery candidates.