6.6.4. HIA File Format

The settings files that support the HTPK Module have an .hia extension. They contain the list of input parameters needed to estimate %Fa and %Fb: molecular weight, solubility, pH, permeability, logP, diffusivity, dose, and other formulation parameters. Various ADMET Property model outputs are commonly found among those inputs.

This file maps default SimXIA (where X depends on species) model parameters onto either collections of appropriate compound attributes in the ADMET Predictor spreadsheet, to ADMET Predictor models, or to some constant. The list of possible parameters is wrapped in XML-style tags to provide maximum flexibility:

<Keyword>Value1|Value2|...|ValueN</Keyword>

In the above, Value1 is the preferred value, while Value2, …, ValueN represent fallback inputs in order of decreasing priority.

A special syntax of semicolon separated string values is reserved for multi-valued properties per compound, such as Dose and pKa.

<Keyword>Value1;Value2;...;ValueN</Keyword>

The file lists a few mandatory input parameters required by the Simulation Module as well as some optional input parameters. The bottom part of the .hia file shows all of the default parameters, some of which can be modified "on the fly" through the appropriate dialogs by providing column names for use in the future. They can also be saved permanently using the "Save" button in the respective dialog. Doing so will make the saved parameters available for subsequent use. Note that saving settings from the dialog modifies the .hia file contained in the AppData/Local folder of the ADMET Predictor installation. The original copy of the file is contained in the ProgramData folder, and is not modified by a Save operation. This allows you to restore default settings should you make a mistake.

The .hia files themselves contain fairly detailed descriptions of what each parameter means. If you need to change parameters which can't be accessed through the dialogs, please read the corresponding .hia file carefully before editing its contents. Changing parameters not accessible through the dialogs is not recommended and should only be carried out in consultation with an expert.

The following table provides a description of the mandatory parameters from the file SimHIA.hia. Nearly identical parameters can be found in the files SimRIA.hia, SimMIA.hia, SimDIA.hia, SimMKYIA.hia, SimDose.hia, SimDoseRat.hia, SimDoseMouse.hia, SimDoseDog.hia and SimDoseMonkey.hia. Please consult these files to see the default values of the various parameters.

Option	Description
ACAT	Name of one file containing ACAT model parameters (usually ACAT.inp; must be in the same folder)
RefMWt	Molecular weight in g/mol
RefFormalQ	Formal electric charge on the molecule, usually AP's descriptor "FormalQ" (unitless integer)
RefFCation	Fraction cationic in aqueous solution at pH = 7.4, usually AP's descriptor "FCation" (unitless fraction)
RefDiff	Bulk diffusivity in water in 10^-5 cm^2/s
RefSolubility	Water solubility in mg/mL at thermodynamic equilibrium
RefSolubilitypH	Reference pH at which the solubility was measured
RefSolFactor	Salt solubility factor
RefPrecipTime	Mean precipitation time in s
RefAllPKa	Either a special value S+pKa indicating results of ADMET Predictor's S+pKa model, or list(s) of semicolon-separated user supplied columns containing ionization constants of all ionizable groups. NOTE: if pKa are specified, all acidic pKa values must be listed before any basic pKa. WARNING: The OptNumAcidicGroups parameter must also be supplied when the pKa are supplied by the user
RefPermeability	Human intestinal effective permeability in 10^-4 cm/s
PeffConversion	Name of conversion function for scaling user-defined permeability to human Peff, or "none" to indicate no scaling. The name (if not "none") must be listed in the system file called PeffConversions.txt; see the Peff Converter section for more information
PeffScalingOn	0/1 flag indicating whether permeability is assumed to be a human value and will be adjusted to reflect the selected species. Note that scaling is performed automatically if RefPermeability is set to the ADMET Predictor model for permeability (S+Peff)
RefLogD	Octanol-water distribution coefficient
RefLogDpH	pH at which octanol-water distribution coefficient was measured (set to -1 for RefLogD = logP)
RefPrUnbnd	Percent unbound in blood plasma in %
AdjustedFupOn	0/1 flag indicating whether RefPrUnbnd should be adjusted to account for non-specific binding to lipids. Note that this setting does not affect the mechanistic volume of distribution, which always uses the adjusted fup. Note also that renal clearance (fup * GFR) is always computed using the non-adjusted fup
RefFumic	Fraction unbound in liver microsomes. This value is used to convert from a bound to an unbound in vitro clearance. Note that this value is used only when RefClearanceSource is "HLM" or "microsomes" and RefClearancePctUnbound is "mechanistic"
RefFuhep	Fraction unbound in hepatocytes. This value is used to convert from a bound to an unbound in vitro clearance. Note that this value is used only when RefClearanceSource is "hepatocytes" and RefClearancePctUnbound is "mechanistic"
RefVd	Volume of distribution in L/kg. The default value of "mechanistic" triggers an internal, mechanistic estimate of Vd using the Lukacova extension of the Rodgers approach
RefFPE	First pass extraction in % or the keyword "mechanistic" indicating estimation of FPE from RefClearance, BodyWeight, and BloodToPlasma
BloodToPlasma	Blood to plasma ratio
RefClearanceSource	"systemic" if total clearance with no contribution from hepatic (first pass) metabolism; "HLM" or "microsomes" if estimated by HLM CLint prediction or experiment; or "hepatocytes" if estimated from the respective in vitro experiments. Renal clearance is set equal to fup*GFR if "HLM", "microsomes," or "hepatocytes" is chosen
RefClearance	Total clearance in L/h/kg (if RefClearanceSource=systemic), or uL/min/mg HLM protein (if RefClearanceSource=HLM), or uL/min/10^6 cells (if RefClearanceSource=hepatocytes)
ClearanceScalingFactor	User-defined value by which intrinsic clearance is multiplied. A value of 1 results in no additional scaling. If the value is "gp_compartmental" (default), the scaling factor is set to 1500/1820, which mimics GastroPlus compartmental simulations that assume a liver weight of 1500g for clearance scaling (for default human). Note that this value is ignored if RefClearanceSource is "systemic"
RefClearancePctUnbound	Percent unbound in the in-vitro clearance experiment. "_unbound_" indicates that RefClearance has already been corrected for binding. "mechanistic" indicates that RefClearance should be corrected automatically; in this case the RefFumic parameter will be used for liver microsomes and the RefFuhep parameter will be used for hepatocytes. "_fup_" indicates that the user-defined fraction unbound in plasma should be used. This option is not available for "systemic" clearance
RenalClearanceOn	0/1 flag indicating whether a renal term should be included in the clearance calculation. If the flag is set to 1, the renal term is computed as Fup*GFR; otherwise, no renal term is included. Note that Fup is always the non-adjusted Fup, even when AdjustedFupOn is set to 1
Dose	Either single dose (numeric or input column), or semicolon separated multiple numerical doses in mg
DosageForm	Immediate-release tablet (IRTablet), immediate-release solution (IRSolution) or IV bolus (IVBolus)
DoseInterval	Dosing interval for repeated dosing in h
NumDoseIntervals	Number of dosing intervals
DoseVolume	Amount of water given with dose in mL
ParticleRadius	API particle radius in microns
ParticleDensity	API particle density in g/mL
BodyWeight	Body weight in kg
RefHydroR	Hydrodynamic radius of molecular ellipsoid, in Angstroms
RefRads	Projected geometrical radius of the molecule, averaged over all orientations, in Angstroms
ParacellularOn	Flag (either 1 or 0) turning paracellular absorption on and off, respectively
RefFaSSIF	Solubility, in mg/mL, in simulated intestinal fluid in fasted state
RefFeSSIF	Solubility, in mg/mL, in simulated intestinal fluid in fed state
BileEffectOn	Flag (either 1 or 0) turning on and off the bile salt influence on solubility, respectively
RefFaPrefix	Default prefix of fraction absorbed column titles
RefFbPrefix	Default prefix of fraction bioavailable column titles