Summary
In a drug discovery environment, reasonable go/no-go humanin-vivo pharmacokinetic (PK) decisions must be made in a timely manner with a minimum amount of animalin-vivo orin-vitro data. We have investigated the accuracy of thein-vivo correlation between rat and human for the prediction of the total systemic clearance (CL), the volume of distribution at steady state (Vss), and the half-life (t1/2) 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 humanin-vivo PK parameters CL, Vss and t1/2 solely from ratin-vivo PK data with acceptable accuracy for making go/no-go decisions in drug discovery. Humanin-vivo PK predictions can be obtained using the simple allometric scaling relationships CLHuman ≈ 40 CLRat (L/hr), Vss Human ≈ 200 Vss Rat (L), and t1/2 Human ≈ 4 t1/2 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 Vss 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 t1/2 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, Vss, and t1/2 are reasonably accurate, easy to remember and simple to calculate, these equations should be useful for making early go/no-goin-vivo human PK decisions for drug discovery candidates.
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Caldwell, G.W., Masucci, J.A., Yan, Z. et al. Allometric scaling of pharmacokinetic parameters in drug discovery: Can human CL, Vss and t1/2 be predicted fromin-vivo rat data?. European Journal of Drug Metabolism and Pharmacokinetics 29, 133–143 (2004). https://doi.org/10.1007/BF03190588
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DOI: https://doi.org/10.1007/BF03190588