Development of predictive pharmacokinetic simulation models for drug discovery

As discovery chemistry produces increased numbers of potential drug compoun ds, the use of ADME (absorption. distribution, metabolism, and excretion) p ropel-ties is becoming increasingly important in the drug selection and pro motion process. A computer simulation model has been developed and validate d to predict ADME outcomes, such as rate of absorption, extent of absorptio n, etc. using a limited number of in vitro data inputs. The oral bioavailab ility of ganciclovir in dogs and humans was simulated using a physiological ly based model that utilized many biopharmaceutically relevant parameters, such as the concentration of ganciclovir in the duodenum, jejunum, ileum, a nd colon at various dose levels and solubility values. The simulations were run and compared to dog and human in vivo data. The simulation results dem onstrated that the low bioavailability of ganciclovir is limited by compoun d solubility rather than permeability due to partitioning as previously spe culated. This technology provides a breakthrough in in silico prediction of absorption and with its continued development and improvement, will aid dr ug discovery and development scientists to produce better pharmaceutical pr oducts. (C) 2000 Elsevier Science B.V. All rights reserved.