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

Abstract

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 (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 human in-vivo PK parameters CL, Vss 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) approximately = 40 CL(Rat) (L/hr), Vss(Human) approximately = 200 Vss(Rat) (L), and t1/2(Human) approximately = 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-go in-vivo human PK decisions for drug discovery candidates.

A Humanized UGT1 Mouse Model Expressing the UGT1A1*28 Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation

“…Although qualitative and quantitative in vitro/in vivo correlation analysis based on data generated using human liver tissues and recombinant enzymes has been applied successfully to many drugs that are cleared by P450-dependent metabolism, these approaches have proven less definitive for glucuronidated compounds, mainly for the reasons alluded to earlier (Soars et al, 2003;Miners et al, 2004;Kilford et al, 2009). In addition, allometric scaling based on in vivo preclinical models has been successful for P450-eliminated drugs, provided that species-specific P450 enzymes have been well studied and understood (Caldwell et al, 2004;De Buck et al, 2007). On the other hand, given the current challenge of using preclinical species to predict human pharmacokinetics for predominantly glucuronidated compounds, more research is required to fully understand species differences and substrate specificity of UGT enzymes.…”

A Perspective on the Prediction of Drug Pharmacokinetics and Disposition in Drug Research and Development

“…In one example, it was determined that simple allometry can accurately predict the elimination rate-constant for irbesartan from animal data (Kumar and Srinivas, 2008). In another study, it was concluded that human half-life values can adequately be predicted from rat half-life values using either linear regression or allometric scaling between human and rat (Caldwell et al, 2004). About 76% and 77% of the values were predicted within an average fold error of less than 3 for the regression and allometric method, respectively.…”

Differences in the neurochemical and behavioural profiles of lisdexamfetamine methylphenidate and modafinil revealed by simultaneous dual-probe microdialysis and locomotor activity measurements in freely-moving rats

“…When a 10-fold factor is applied to take into account the allometric and pharmacokinetic differences between humans and rats (Caldwell et al, 2004), these doses would translate to oral doses in rats of 10-13 mg/kg for lisdexamfetamine dimesylate, 3.0-5.0 mg/kg for methylphenidate hydrochloride and 100-150 mg/kg for modafinil, which are similar to those employed in this experimental study.…”