WinPBPK-A Software for Physiologically-based Pharmacokinetic Model Analysis: Application to Tissue and Organ Distribution Analysis of Tacrolimus.

Abstract

Summary: WinPBPK is a computer program for the analysis of drug distribution in the body which utilizes a physiologically-based pharmacokinetic model, where linear ordinary differential equations are numerically solved by the Runge-Kutta-Gill method. This program is written in Visual BASIC (VB) language. Since VB runs under Windows and has a high level user interface, WinPBPK is available to all DOS/V IBM compati ble computers. Numerically solved tissue or organ drug concentrations vs. time data are shown on the CRT display as concentrations vs. time curves and thereafter are saved on hard disk. These numerical data can also be shown as simulated image whole body autoradiograms where drug concentrations in all the tissues or organs are converted to monochrome or full color image data. These image data can be visually com pared to that obtained by real autoradiography using 14C-labelled drug. The system was applied to the phar macokinetic analysis of tacrolimus, an immunosuppressant, in rats. The PBPK model for tacrolimus was de veloped with 17 tissues and organs including lung, blood, brain, heart, liver, pancreas, spleen, intestine, kid neys, gall bladder, thyroid, fat tissue, muscle, testes, bone and skin. The exchange rate of the amount of drug in each tissue or organ was described with differential equations using physiological parameters, biochemical parameters and pharmacokinetic parameters. The simulated image autoradiograms of tacroli mus at 15 min, 1 hr, 3 hr, and 8 hr after iv bolus injection to rats, 1 mg/kg, were compared with the au toradiograms of 14C tacrolimus being injected to rats, 1 mg/kg. There was good correlation between the simulated image autoradiograms and the real ones. By means of this software, the predicted pattern of drug distribution to the tissues and organs based on the PBPK model analysis can be compared visually to the real autoradiogram.

ADME Screening

“…PBPK models use a range of parameters from in silico, in vitro, and in vivo data and the inputs can be adapted as a compound progresses through the discovery and development process and more wet data become available [114][115][116][117]. PBPK models are based on mechanistic, multicompartment models, with compartments corresponding to predefined organs or tissues, with interconnections corresponding to blood or lymph flows.…”