Preclinical pharmacokinetics and interspecies scaling of ragaglitazar, a novel biliary excreted PPAR dual activator

Allometric scaling has been used as an effective tool for the prediction of human pharmacokinetic parameters. Allometry has been a useful approach for the analysis of compounds that are eliminated unchanged in the urine and/or exhibit similar metabolic patterns across species. However, it has been a challenging issue to correctly predict human pharmacokinetic parameters for drugs that are eliminated intact and/or as conjugates in the bile. Ragaglitazar is a novel, non-thiazolidinedione peroxisome proliferator-activated receptor (PPAR) alpha- and gamma-agonist. In our investigation, preclinical pharmacokinetic data on ragaglitazar were gathered for several animal species (mice, rats, rabbits and dogs). Ragaglitazar when administered orally has shown a low clearance rate (Cl/F; < 5% of hepatic blood flow) in mice, rats and rabbits and a moderately high Cl/F in dogs (> 15% of hepatic blood flow). A qualitative estimation of rat bile has unequivocally confirmed the elimination of ragaglitazar in the bile. The human pharmacokinetic data are also indicative of the involvement of enterohepatic biliary recycling. In order to predict key parameters such as Cl/F and volume of distribution (V/F), simple allometry was the approach adopted at the onset. Although V/F scaled adequately, it failed to accurately predict human Cl/F. Therefore, standard correction factors such as maximum life span potential (MLP) and brain weight were also included. Although such modifications improved the linearity (r2 > 0.9), they failed to predict the investigated values. Further incorporation of correction factors particularly relevant to biliary excreted drugs improved the prediction of these values. Interestingly, the exclusion of dog data from the interspecies scaling considerably improved the prediction of both Cl/F and V/F.