Application of allometry principles for the prediction of human pharmacokinetic parameters for irbesartan, a AT1 receptor antagonist, from animal data

Abstract

Allometric principles have been applied to scale and predict human pharmacokinetic parameters of irbesartan, an important AT1 receptor antagonist. The preclinical data gathered from rats, macaques (monkeys) and dogs were used in the allometric analysis. The use of these species was rationalized because preclinical models based on these species have been used in the evaluation pharmacodynamic activity of irbesartan. The human parameter values for clearance (CL/F), volume of distribution (V/F), and elimination rate constant (Kel) were scaled using simple allometry (CL/F, V/F and Kel) or with correction factors (CL/F). The predictions of both CL/F and elimination half life (T1/2) (using Kel) for irbesartan appeared to be in close proximity to the respective human reported values (CL/F: predicted=18 L/h, observed=22.2 L/h; T1/2: predicted = 9 h; observed = 10-20 h); while, V/F value was marginally over predicted by 1.75-fold using simple allometry (predicted = 456 L; observed = 260 L). The present work presents an opportunity for prospective allometric scaling for the compounds belonging to this important therapeutic class.