Prediction of pharmacokinetics prior to in vivo studies. II. Generic physiologically based pharmacokinetic models of drug disposition.
Many in vitro data on physicochemical properties and specific absorption, distribution, metabolism, and elimination (ADME) processes are already available at early stages of drug discovery. These data about new drug candidates could be integrated/connected in physiologically based pharmacokinetic (PBPK) models to estimate a priori the overall plasma and tissue kinetic behaviors under in vivo conditions. The objective of the present study was to illustrate that generic PBPK models integrating such data can be developed in drug discovery prior to any in vivo studies. This approach was illustrated with three example compounds, including two lipophilic bases (diazepam, propranolol) and one neutral more hydrophilic drug (ethoxybenzamide). Distribution and liver metabolism were the processes integrated in the generic rat PBPK models of disposition. Tissue:plasma partition coefficients (P(t:p)s) used for description of distribution were estimated from established tissue composition-based equations, which need only in vitro data on drug lipophilicity and plasma protein binding as sole input parameters. Furthermore, data on intrinsic clearance (CL(int)) determined in vitro with hepatocytes were scaled to the in vivo situation to estimate hepatic metabolic clearance. These prediction approaches were both incorporated in the PBPK models to enable automated estimation of distribution and liver metabolism for each drug studied. The generic PBPK models suggested can simulate a priori concentration-time profiles of plasma and several tissues after intravenous administrations to rat. The results indicate that most of the simulated concentration-time profiles of plasma and 10 tissues are in reasonable agreement with the corresponding experimental data determined in vivo (less than a factor of two). However, some more relevant deviations were observed for specific tissues (brain and gut for diazepam; liver and gut for ethoxybenzamide; lung for propranolol) because of important ADME processes were probably neglected in the PBPK models of these drugs. In this context, generic PBPK models were also used for mechanistic evaluations of pharmacokinetics for generating research hypotheses to understand these deviations. Overall, the present generic and integrative PBPK approach of drug disposition suggested as a tool for a priori simulations and mechanistic evaluations of pharmacokinetics has the potential to improve the selection and optimization of new drug candidates.
Poulin
Patrick
P
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Non-Clinical Development--Drug Safety, PRNS Bau: 69/101, CH-4070 Basel, Switzerland. patrick.poulin@roche.com
Theil
Frank-Peter
FP
D000818:Animals; D001549:Benzamides / Q000097:blood / Q000493:pharmacokinetics*; D003975:Diazepam / Q000097:blood / Q000493:pharmacokinetics; D005019:Ethyl Ethers / Q000097:blood / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010599:Pharmacokinetics; D011433:Propranolol / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution
D001549:Benzamides; D005019:Ethyl Ethers; D011433:Propranolol; D003975:Diazepam