Norris D A [a]. Leesman G D. Sinko P J. Grass G M.
Development of predictive pharmacokinetic simulation models
for drug discovery, Journal of Controlled Release 65(1-2) :55-62, 2000.
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.
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