6.6. Simulation Theory and Details
The HTPK Simulation Module is a streamlined version of the Advanced Compartmental Absorption and Transit (ACAT) model of drug absorption employed in our GastroPlus software. Compound dissolution, permeation, transit, and regional property dependence along the intestinal tract are all taken into account, as is hepatic and passive renal clearance. The physiologies used correspond to the Rat-Physiological-Fasted, Human-Physiological-Fasted, Mouse-Physiological-Fasted Dog-Physiological-Fasted and Monkey-Physiological-Fasted physiologies in GastroPlus. Users are encouraged to consult GastroPlus documentation for further details.
This module has been designed to provide drug discovery scientists with estimates of rat, human, mouse, dog or monkey intestinal absorption (%Fa) or bioavailability (%Fb) for compounds even before the compounds have been synthesized. Keeping up with other ADMET Predictor features in terms of speed, the HTPK Simulation module calculates these pharmacokinetic properties very quickly and doesn't require special expertise for use. If you are interested in complex simulations, you should try using GastroPlus instead of the HTPK Simulation Module.
Just as for absorption and bioavailability simulations run in GastroPlus, HTPK predictions depend on various input parameters that can be broadly divided into three groups:
-
Physiological Parameters
Each of the compartments that make up the gastrointestinal (GI) tract has a characteristic length, radius, paracellular pore size, transit time, regional pH, etc. any of which can vary with the species of interest. Values for these System-Related Input Parameters represent a priori knowledge of the anatomy and physiology of the corresponding organism’s GI tract. These parameters have been well-established within GastroPlus and have been used in ADMET Predictor, unchanged. The parameters are stored in the ACAT.inp, RatACAT.inp, MouseACAT.inp, DogACAT.inp and MonkeyACAT.inp settings files.
-
Formulation Parameters
Input parameters related to formulation, such as DoseVolume = 250 mL (human), ParticleRadius = 25 µm, etc. are set to constant values. They are stored in the SimRIA.hia, SimHIA.hia, SimMIA.hia, SimDIA.hia, SimMKYIA.hia, SimDoseRat.hia, SimDose.hia, SimDoseMouse.hia, SimDoseDog.hia and SimDoseMonkey.hia settings files. Some but not all of these parameters can be modified in the Simulate fraction absorbed..., Estimate dose... or Advanced simulation parameters dialog boxes.
-
Compound-related Input Parameters.
These include all parameters specific for a particular compound. Physicochemical properties such as lipophilicity, solubility, molecular weight (MW), and pKa values are independent of organism physiology. Biochemical properties such as fraction of drug unbound, ratio of blood to plasma or tissue-plasma partition coefficient, though drug-specific, are defined by the interaction between the drug and the biological system, so they are dependent on both the drug and the organism.
Biorelevant solubility, effective permeability and volume of distribution values are used to characterize how a compound distributes through different compartments.
Further details related to simulations are provided in the topics below: