Journal of Controlled Release 65 (2000) 55–62 www.elsevier.com / locate / jconrel Development of predictive pharmacokinetic simulation models for drug discovery a, a a,b a * D.A. Norris , G.D. Leesman , P.J. Sinko , G.M. Grass a Trega Biosciences, 9880 Campus Point Dr., San Diego, CA 92121, USA b College of Pharmacy, Rutgers University, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA Received 26 June 1999; accepted 10 July 1999 Abstract As discovery chemistry produces increased numbers of potential drug compounds, the use of ADME (absorption, distribution, metabolism, and excretion) properties is becoming increasingly important in the drug selection and promotion process. A computer simulation model has been developed and validated to predict ADME outcomes, such as rate of absorption, extent of absorption, etc. using a limited number of in vitro data inputs. The oral bioavailability of ganciclovir in dogs and humans was simulated using a physiologically based model that utilized many biopharmaceutically relevant parameters, such as the concentration of ganciclovir in the duodenum, jejunum, ileum, and colon at various dose levels and solubility values. The simulations were run and compared to dog and human in vivo data. The simulation results demonstrated that the low bioavailability of ganciclovir is limited by compound solubility rather than permeability due to partitioning as previously speculated. This technology provides a breakthrough in in silico prediction of absorption and with its continued development and improvement, will aid drug discovery and development scientists to produce better pharmaceutical products.  2000 Elsevier Science B.V. All rights reserved. Keywords: Ganciclovir; Simulation models; Bioavailability; Humans; Dogs 1. Introduction are promoted to development and screened for ADME properties (oral absorption or permeability, Within the drug discovery environment, drug distribution, metabolic stability, and excretion) or compounds must be selected based on their potential toxicity using numerous animal or in vitro models. for success as a new drug product. The selection Compounds which fail to demonstrate satisfactory process, or screening, is classically accomplished ADME properties are removed from consideration as using animal and/or in vitro model systems to drug candidates. Prentis [1] observed, for a 20 year determine the receptor-based activity profile for each period (1968–1988), the primary reasons that drug candidate compound. Traditionally, promising drug candidates were dropped from development were candidates with acceptable receptor-based activity pharmacokinetic difficulties in man and a lack of efficacy. In 1997, this conclusion was confirmed by Kennedy who reported that the termination of the *Corresponding author. Tel.: 11-858-410-6685; fax: 11-858- development of drug candidates other than for 410-6665. E-mail address: dnorris@trega.com (D.A. Norris) efficacy was poor pharmacokinetic (or ADME) 0168-3659 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0168-3659(99)00232-1