Pharmacokinetics View

Input/Option

Description

Compound

A drop-down. Selects the current compound. Options are populated based on compounds already added to the project.

If no compounds have been added, this will be blank. If no compound is selected, the panels below will be disabled.

Physiology

A drop-down. Selects the current physiology, populated based on physiologies added to the project.

If no physiologies have been added, this will be blank. If no physiology is selected, the panels below will be disabled.

Blood Plasma Concentration Ratio

The blood to plasma concentration ratio for the selected compound-physiology pair. The value can be edited.

Experimental f_up

• The fraction unbound in plasma for the selected compound-physiology pair, as a percentage. The value can be edited.

• The toggle, which is off by default, can be switched on to enable the use of the Experimental f_up for K_p calculations for PBPK and in the simulation. If turned on, the Lipid Adjusted f_up will be automatically off.

Lipid Adjusted f_up

• The Experimental f_up automatically adjusted by the program for possible binding to plasma lipids. This value cannot be edited.

• The toggle, which is on by default, indicates that the Lipid Adjusted f_up will be used for K_p calculations for PBPK and in the simulation. If turned on, the Experimental f_up will be automatically off.

Note: Experimental f_up is used to calculate kidney filtration clearance when f_up*GFR is selected as the method, regardless of the setting of the toggle above.

Note: This f_up adjustment assumes that Experimental f_up is an accurate measure of drug binding to plasma proteins and that logP can be used as a measure of drug binding to plasma lipids.

Input/Option

Description

Scale F_up and R_bp

A toggle. Turned off by default.

Must be turned on for specific populations to enable the scaling of the entered values of R_bp and Experimental F_up.

When the toggle is turned off, there is no scaling of R_bp and Experimental F_up values, and those displayed in the Current Physiology column are identical to those in the general settings in the main view.

When the toggle is turned on, the scaled values of R_bp and Experimental F_up are shown in the Current Physiology column and are also visible in the main view and cannot be edited.

Scale F_up and R_bp table

Lists the relevant parameters (see below) for a Healthy Adult, in the left-hand column and the Current Physiology, in the right-hand column.

If Scale F_up and R_bp is toggled off, the F_up and R_bp values in the Healthy Adult and Current Physiology columns will be identical.

For Pregnant physiologies, the parameters for the fetus are also displayed.

Hematocrit

Healthy Adult: The default hematocrit for a healthy adult. The value cannot be edited.

Current Physiology /Fetal: The default hematocrit for the current physiology. The value can be edited.

Blood/Plasma Concentration Ratio

Healthy Adult: The R_bp for the selected compound paired with a healthy adult physiology. The value can be edited if Scale F_up and R_bp is toggled On.

Current Physiology / Fetal: The scaled R_bp for the scaled compound-physiology pair, calculated based on the difference in the hematocrit. The value can’t be edited.

Plasma Protein (% of healthy adult)

Healthy Adult: The default amount of plasma protein, expressed as a percentage. The value can’t be edited.

Current Physiology / Fetal: The default amount of plasma protein, for the current physiology, expressed as a percentage of the total plasma protein of a healthy adult. The value can be edited.

Plasma F_up (%)

Healthy Adult: The F_up for the selected compound paired with a healthy adult physiology. The value can be edited if Scale F_up and R_bp is toggled On.

Current Physiology / Fetal: The scaled F_up for the current compound-physiology pair, calculated based on the difference in plasma proteins. The value can’t be edited.

Adjusted Plasma F_up (%)

Healthy Adult: The Experimental f_up automatically adjusted by the program for possible binding to plasma lipids. This value cannot be edited.

Current Physiology / Fetal: The scaled f_up automatically adjusted by the program for possible binding to plasma lipids. This value cannot be edited.

Input/Option

Description

Liver Blood Flow

The liver blood flow used in the compartmental model, for the species selected above. This value and the units (L/h, mL/min, mL/s, L/min) can be edited.

This is a property of the physiology selected at the top of the Pharmacokinetics view and will be used in any simulations utilizing that physiology (see Drug Administration panel).

Compartmental parameters table

Displays the available compartmental models and the associated parameters.

Note: for parameters where normalizing by bodyweight is an option (General and Renal Clearance, V_c, V₂ and V₃), selecting the per kg option (by clicking on the units in the header and checking the white box) will normalize all values in that column by the bodyweight of the species selected above. Unchecking the box will recalculate the base values, also based on the bodyweight of the species selected above.

Model Name

The name associated with the compartmental parameters in the given row. This name will be displayed for selection in the Simulation view (see Compound Settings panel). The name can be edited using the Rename button (see below).

Compartmental models fitted in PKPlus™ and transferred here (See PKPlus™ Module) will be named automatically based on the PKPlus™ Run name and the number of compartments.

Compartments

A drop-down. Selects the number of compartments to be used for the compartmental model (one, two or three).

General Clearance

The clearance from the central compartment. The value and the units (L/h, mL/min, mL/s, L/h/kg, mL/min/kg, mL/s/kg) can be edited. See note above (Compartmental parameters table) when normalizing by bodyweight.

Renal Clearance

The rate of renal clearance. The value and the units (L/h, mL/min, mL/s, L/h/kg, mL/min/kg, mL/s/kg) can be edited. See note above (Compartmental parameters table) when normalizing by bodyweight.

This clearance is also from the central compartment and is separated from General Clearance to enable estimation of liver FPE.

V_c

The volume of the central compartment. The value and the units (L, mL, L/kg, mL/kg) can be edited. See note above (Compartmental parameters table) when normalizing by bodyweight.

For one-compartment drugs, this is the same as the total volume of distribution, Vd. For multi-compartment drugs, this is the central compartment volume, Vc.

t_½

The terminal half-life calculated based on the other parameters entered. Neither the value nor the units may be edited.

k₁₂ / k₂₁ / k₁₃ / k₃₁

The micro-constants for distribution of drug to and from the second and third compartments, if used. The value and the units (1/h, 1/min) can be edited.

V₂ / V₃

The volumes for the second and third pharmacokinetic compartments, if used, calculated based on the micro-constants entered. The value cannot be edited but the units (L, mL, L/kg, mL/kg) can be edited. See note above (Compartmental parameters table) when normalizing by bodyweight.

Add

Adds a compartmental model to the table - activates the Enter model name: input box to name the new model.

Rename

Renames the currently selected compartmental model - activates the Enter the new model name: input box to rename the model.

Delete

Deletes the currently selected compartmental model – Hold Ctrl-key and click to select the row containing the model for deletion.

Input/Option

Description

Set all tissues to:

Two buttons that will change all tissues in the model to Perfusion Limited or Permeability Limited, respectively.
Perfusion Limited tissues have a purple border in the PBPK diagram, whilst the border of Permeability Limited tissues is green.

Lymphatic Circulation

A toggle. Turned off by default. Turn on (the toggle will go green) to include the lymphatic circulation in the PBPK model. This setting should be activated for small molecules if this process contributes significantly to the drug’s disposition.

Use Specific PStc

A toggle. Turned off by default. Turn on to use the Specific PStc, together with the total cell volume of each tissue, to calculate the PStc for any permeability limited tissues in the model.

Specific PStc

The value, in (mL/s)/mL, of the Specific PStc. The value can be edited.

Input/Option

Description

Custom Name

The name of the custom tissue. Type the desired name in the input field and click “Add”.

The added custom tissue will show up at the bottom of PBPK diagram.

Input/Option

Description

Remove

Deletes the tissue selected in the PBPK model.

Perfusion limited

Changes the tissue model to Perfusion Limited

Permeability limited

Changes the tissue model to Permeability Limited

Input/Option

Description

Tissue Type

A drop-down. Selects whether the individual tissue is perfusion or permeability limited.

This selection may also be changed by right clicking on the tissue in the interactive diagram or from the Tissue Type drop-down in the PBPK table (see below).

Perfusion Limited tissues have a purple border in the interactive diagram, whilst the border of Permeability Limited tissues is green.

k_p

The tissue to plasma partition coefficient (k_p) for the selected tissue. This value can be edited.

For perfusion limited tissues this determines the concentration of drug in the tissue.

For permeability limited tissues this determines the concentration of drug in the extracellular compartment.

f_ut

The fraction unbound in the tissue for a perfusion limited tissue, or the fraction unbound in the intracellular compartment for a permeability limited tissue. These values can be edited.

f_u,ext

The fraction unbound in the extracellular compartment for a permeability limited tissue. Only active when the selected tissue is permeability limited. This value can be edited.

CLint

The unbound intrinsic clearance for the selected tissue. The value and the units can be edited (L/h, mL/min, mL/s, L/min). If the value is edited here, the PBPK table automatically updates (see below)

K_elf/p,u

The epithelial lining fluid (ELF) / unbound plasma partition coefficient.

Active for lung only. Used to calculate the amount of drug in the ELF assuming instant partitioning when the lung is perfusion limited. The value can be edited.

f_u ELF

The fraction unbound in the epithelial lining fluid.

Active for lung only. This value can be edited.

Basolateral PStc

Basolateral Permeability-Surface Area product for passive diffusion between extracellular and intracellular compartments.

Active when a tissue is permeability limited.

If Use Specific PStc is toggled Off, the value and the units (mL/s, L/h) can be edited.

If Use Specific PStc is toggled On, this value is calculated based on specific PStc and cannot be edited.

Apical PStc

Apical Permeability-Surface Area product for passive diffusion between tissue or intracellular compartment and ELF, kidney tubules or bile for the lung, kidney and liver, respectively. Used to calculate the amount of drug in the ELF assuming slow diffusion.

Active for lung, liver and kidney whether the tissue is perfusion limited or permeability limited.

If Use Specific PStc is toggled Off, the value and the units (mL/s, L/h) can be edited.

If Use Specific PStc is toggled On, this value is calculated based on specific PStc and cannot be edited, with the exception of liver.

Renal Systemic Clearance

The systemic renal clearance. The value is calculated based on the filtration clearance, the intrinsic clearance and the clearance due to passive secretion and reabsorption (where applicable). The units can be edited (L/h, mL/min, mL/s, L/min).

Visible for kidney and fetal tissues only.

Use Instant Partitioning

A toggle. On by default. Turning it off for one tissue turns it off for all tissues.

Input/Option

Description

CLint

The unbound intrinsic clearance for the selected compartment. The value and the units can be edited (L/h, mL/min, mL/s, L/min). If the value is edited here, the PBPK table automatically updates (see below).

Active for Venous Return, Arterial Supply, Fetal Venous Return and Fetal Arterial Supply.

Input/Option

Description

Volume

The total volume of the selected tissue. The value and the units (mL, L) can be edited.

Blood Flow

The blood flow of the selected tissue. The value and the units (L/h, mL/min, mL/s, L/min) can be edited.

Lymph Flow Fraction

The lymphatic flow of the selected tissue as a percentage of plasma flow. The value can be edited.

FcRn Conc

The concentration of neonatal Fc receptor in the selected tissue in umol/L. The value can be edited.

Neutral Lipid Fraction

The neutral lipid content of the selected tissue expressed as a fraction of the wet tissue weight. The value can be edited.

Phospholipid Fraction

The phospholipid content of the selected tissue expressed as a fraction of the wet tissue weight. The value can be edited.

Water Fraction

The water content of the selected tissue expressed as a fraction of the wet tissue weight. The value can be edited.

Acidic Phospholipid Fraction

The concentration of acidic phospholipids in the selected tissue. The value and the units (mg/g, g/g) can be edited.

Interstitial Volume Fraction

The volume of the interstitial space for the selected tissue expressed as a fraction of the total tissue volume. The value can be edited.

Vascular Volume Fraction

The volume of the vascular space for the selected tissue expressed as a fraction of the total tissue volume. The value can be edited.

Density

The tissue density for the selected tissue. The value and the units (g/mL, mg/L, mg/mL) can be edited.

Epithelial Lining Fluid Volume

Visible for lung only.

The volume of the epithelial lining fluid in the lung. The value and the units (mL, L) can be edited.

Epithelial Lining Fluid pH

Visible for lung only.

The pH of the epithelial lining fluid in the lung. The value can be edited.

Mucociliary Clearance

Visible for lung only.

The mucociliary clearance rate in the lung. The value and the units (mL/s, mL/min, L/h, L/min) can be edited.

Endosomal Volume Fraction

The volume of the endosomal space for the selected tissue expressed as a fraction of the total tissue volume. The value can be edited.

Albumin Ratio

The albumin tissue to plasma concentration ratio for the selected tissue. This is set as specified in the Tissue Albumin drop-down in the Advanced Options sub-panel (see Advanced Options sub-panel below).

Leakage

The level of leakage from the vasculature of the selected tissue using muscle as a reference (=1). A value <1 indicates a leaky tissue, a value >1 indicates a tight tissue. The value can be edited.

Lysosomal Volume Fraction

The volume of the lysosomes for the selected tissue expressed as a fraction of the total tissue volume. The value can be edited.

Lysosomal pH

The pH of the lysosomes in the selected tissue. The value can be edited.

Input/Option

Description

Swallowing Rate

The fetal swallowing rate. The value and the units (mL/s, mL/d, mL/min, L/h, L/min) can be edited.

Relevant for Amniotic Fluid only.

Secretion Rate

The secretion rate from the fetal tissue. The value and the units (mL/s, mL/d, mL/min, L/h, L/min) can be edited.

Relevant for Amniotic Fluid only.

Transmembraneous Rate

The transport rate between the amniotic fluid and uterus wall. The value and the units (mL/s, mL/d, mL/min, L/h, L/min) can be edited.

Relevant for Amniotic Fluid only.

Intramembraneous Osmotic Rate

The passive transport rate of the solute and water between the amniotic fluid and fetal blood which occurs in placenta, fetal skin and umbilical cord. Related to osmolarity. The value and the units (mL/s, mL/d, mL/min, L/h, L/min) can be edited.

Relevant for Amniotic Fluid only.

Intramembraneous Vesicular Rate

The active transport rate of the solute and water between the amniotic fluid and fetal blood which occurs in placenta, fetal skin and umbilical cord. Driven by vesicular pressure. The value and the units (mL/s, mL/d, mL/min, L/h, L/min) can be edited.

Relevant for Amniotic Fluid only.

Placental Villi Area

The surface area of the placental villi in m². The value can be edited.

Relevant for Placental Fetal only.

Input/Option

Description

Volume

The total volume of the selected compartment. The value and the units (mL, L) can be edited.

Blood Flow

The blood flow of the selected compartment. The value and the units (L/h, mL/min, mL/s, L/min) can be edited.

This is the only parameter in this table that applies to Hepatic Artery and Tissue Gut.

Plasma Parameters

The following parameters all apply to plasma fraction of the compartment.

Fraction Neutral Lipid

The neutral lipid content of plasma. The value can be edited.

Fraction Phospholipid

The phospholipid content of plasma. The value can be edited.

Fraction Water

The water content of plasma. The value can be edited.

Hematocrit

The hematocrit. The value can be edited.

Plasma Protein

The total plasma protein expressed as a percentage of the typical adult amount. The value can be edited.

Blood Cell Parameters

The following parameters all apply to the blood cell fraction of the compartment.

Fraction Neutral Lipid

The neutral lipid content of red blood cells. The value can be edited.

Fraction Phospholipid

The phospholipid content of red blood cells. The value can be edited.

Fraction Intracellular Water

The intracellular water content of red blood cells. The value can be edited.

Note: the extracellular water content is equal to 0.

Concentration of Acidic Phospholipids

The concentration of acidic phospholipids in red blood cells in grams per gram of tissue. The value can be edited.

Input/Option

Description

Kidney Filtration Method

A drop-down. Selects the method used to calculate the filtration clearance: f_up * GFR (the unbound glomerular filtration rate), Glomerular Filtration Rate (GFR), Fraction Blood Flow, or User Specified. The method selected determines which of the following parameters are visible.

Urine Flow

The urine flow rate. The value and the units (L/h, mL/min, mL/s, L/min) can be edited.

Glomerular Filtration Rate (GFR)

The glomerular filtration rate. The value and the units (L/h, mL/min, mL/s, L/min) can be edited. This value is used as the filtration clearance when Glomerular Filtration is selected as the Kidney Filtration Method.

f_up * GFR

The calculated unbound glomerular filtration rate (mL/s). Calculated by multiplying the experimental fraction unbound in the plasma for the selected compound in the selected physiology by the GFR determined above. Neither the value nor the units can be edited.

Note that this calculation always uses Experimental f_up, not Lipid Adjusted f_up, regardless of the selection in the general settings.

Visible when f_up * GFR is selected as the Kidney Filtration Method.

Tubule Volume

The volume of the kidney tubules. The value and the units (mL, L) can be edited.

User Defined Filtration Clearance

The filtration clearance (L/h). The value can be edited and is then used as entered to determine the filtration clearance when the Kidney Filtration Method is set to User Defined.

Setting this value to 0 will effectively disable renal filtration clearance.

Visible when User Defined is selected as the Kidney Filtration Method.

Calculated Filtration Clearance

The calculated filtration clearance (mL/s). Calculated by multiplying kidney blood flow, as defined in the Physiology sub-panel above, by the Fraction of Blood Flow. Neither the value nor the units can be edited.

Visible when Fraction Blood Flow is selected as the Kidney Filtration Method.

Fraction of Blood Flow

The fraction of kidney blood flow to be used to calculate the filtration clearance. This value can be edited when Fraction Blood Flow is selected as the Kidney Filtration Method.

Input/Option

Description

Enzyme

Indicates the enzyme for which expression information is shown. Different enzymes may be selected using the drop-down.

Phenotype

The phenotype of the indicated enzyme. A different phenotype may be selected using the drop-down (Wild, Poor, Intermediate, Extensive, Ultra) however, for enzymes where the change in Expression is not available it will need to be updated manually.

Expression

The expression of the enzyme in the selected tissue. This value, multiplied by the tissue mass, is then multiplied by the PBPK V_max in the Enzyme Kinetics table to get the final V_max used in the simulation. The value and the units (mg enzyme/g tissue, µg/g, mg/kg, µg/kg) can be edited.

Expression CV

The covariance of the expression for the indicated enzyme in the selected tissue. The value can be edited.

Turnover Rate

The turnover rate of the indicated enzyme in the selected tissue. The value and the units (1/min, 1/h, 1/s) can be edited.

Expression Source

The source of the expression levels of the indicated enzyme in the selected tissue. Values that have been edited from the default, or custom enzymes, will have a source of User-Defined. Otherwise, the source will reflect the physiology the expression was derived from.

All/Active

A toggle. Controls whether the enzymes shown will be filtered based on the compound selected at the top of the Pharmacokinetics view.

Add

Add an enzyme entry for the species of the current physiology. Once the enzyme is created, it will be added automatically as a row to the table.

Enzymes added here must still be assigned to the intended compound using the Enzyme Kinetics table on the Compounds view.

Custom

Add a custom enzyme for the species of the current physiology. Once the custom enzyme is created, it will be added automatically as a row to the table. It will also be available thereafter in the enzyme drop-down for selection.

Custom enzymes added here must still be assigned to the intended compound using the Enzyme Kinetics table on the Compounds view.

Delete

Delete the selected row from the table. Hold Ctrl-key and click anywhere in the row to select the row for deletion.

Input/Option

Description

Transporter

Indicates the transporter for which expression information is shown. Different transporters may be selected using the drop-down.

Expression

The expression of the transporter in the selected tissue. This value, multiplied by the tissue mass, is then multiplied by the PBPK V_max in the Transporter Kinetics table to get the final V_max used in the simulation. The value and the units (mg transporter/g tissue, µg/g, mg/kg, µg/kg) can be edited.

Flux Type

Indicates the flux direction (influx or efflux) for the transporter. Flux type may be changed using the drop-down.

Membrane

Indicates the membrane location (apical or basolateral) for the transporter. Membrane location may be changed using the drop-down.

Turnover Rate

The turnover rate, of the indicated transporter in the selected tissue. The value and the units (1/min, 1/h, 1/s) can be edited.

Expression Source

The source of the expression levels of the indicated transporter in the selected tissue. Values that have been edited from the default, or custom transporters, will have a source of User-Defined. Otherwise, the source will reflect the physiology the expression was derived from.

All/Active

A toggle. Controls whether the transporters shown will be filtered based on the compound selected at the top of the Pharmacokinetics view.

Add

Add a transporter entry for the species of the current physiology. Once the transporter is created, it will be added automatically as a row to the table.

Transporters added here must still be assigned to the intended compound using the Transporter Kinetics table on the Compounds view.

Custom

Add a custom transporter for the species of the current physiology. Once the custom transporter is created, it will be added automatically as a row to the table. It will also be available thereafter in the transporter drop-down for selection.

Custom transporters added here must still be assigned to the intended compound using the Transporter Kinetics table on the Compounds view.

Delete

Delete the selected row from the table. Hold Ctrl-key and click anywhere in the row to select the row prior to deletion.

Input/Option

Description

Calculate Tissue K_p

A button. Clicking causes the K_p for each tissue to be recalculated using the methods selected in the sub-panels (see below) and the compound inputs.

Note: The K_ps will not be recalculated based on theoretical values if User Defined is selected as the K_p calculation method (see below).

Tissue

Identifies the tissue or circulatory compartment to which all other information in the row applies. The tissues are listed in alphabetical order.

Tissue Type

A drop-down. Selects whether the individual tissue is perfusion or permeability limited.

K_p

The partition coefficient (k_p) for the selected tissue. This value can be edited.

For perfusion limited tissues this determines the concentration of drug in the tissue.

For permeability limited tissues this determines the concentration of drug in the extracellular compartment.

CL

The systemic plasma clearance of the compound in the specified tissue. Calculated from the CL_int (see below). The value and the units can be edited (L/h, mL/min, mL/s, L/min). Editing the value causes a recalculation of the CL_int so the two values remain aligned.

Note: assigning a CL in one circulatory compartment (arterial supply or venous return) will automatically enter the same clearance in the other circulatory compartment.

Cl_int

The unbound intrinsic clearance. The value and the units can be edited (L/h, mL/min, mL/s, L/min). Editing the value causes a recalculation of the CL so the two values remain aligned.

Note: assigning a CL_int in one circulatory compartment (arterial supply or venous return) will automatically enter the same clearance in the other circulatory compartment.

Apical PStc

Apical Permeability-Surface Area product for passive diffusion between tissue or intracellular compartment and ELF, kidney tubules or bile for the lung, kidney, and liver, respectively. Used to calculate the amount of drug in the ELF assuming slow diffusion.

Active for lung, liver and kidney whether the tissue is perfusion limited or permeability limited.

If Use Specific PStc is toggled Off, the value and the units (mL/s, L/h) can be edited.

If Use Specific PStc is toggled On, this value is calculated based on specific PStc and cannot be edited, with the exception of liver.

Basolateral PStc

Basolateral Permeability-Surface Area product for passive diffusion between extracellular and intracellular compartments.

Active when a tissue is permeability limited.

If Use Specific PStc is toggled Off, the value and the units (mL/s, L/h) can be edited.

If Use Specific PStc is toggled On, this value is calculated based on specific PStc and cannot be edited.

F_ut

The fraction unbound in the tissue for a perfusion limited tissue. These values can be edited.

F_u,int

The fraction unbound in the intracellular compartment for a permeability limited tissue. Only active when the selected tissue is permeability limited. This value can be edited.

F_u,ext

The fraction unbound in the extracellular compartment for a permeability limited tissue. Only active when the selected tissue is permeability limited. This value can be edited.

Volume

The volume of the indicated tissue.

The value and the units (mL, L) can be edited.

Blood Flow

The blood flow of the selected tissue. The value and the units (L/h, mL/min, mL/s, L/min) can be edited.

Lymph Flow

The lymphatic flow of the selected tissue. The value and the units (L/h, mL/min, mL/s, L/min) can be edited.

Input/Option

Description

K_p Method

A drop-down. Selects the method used to calculate the partition coefficient (k_p) for perfusion limited tissues.

The following methods are available:

• Lukacova (default)

• Berezhkovskiy

• Poulin, Theil – Homogeneous

• Poulin, Theil – Extracellular

• Rodgers, Leahy, Rowland

• Lukacova with Lysosomes

• User Defined

If User Defined is selected, the Calculate Tissue K_p button will not work.

f_ut Method

A drop-down. Selects the method used to calculate the fraction unbound in the tissue for perfusion limited tissues.

The following methods are available:

• Kp Based (default)

• Lukacova v1

• Poulin

Input/Option

Description

K_p Method

A drop-down. Selects the method used to calculate the partition coefficient (k_p) for permeability limited tissues.

The following methods are available:

• Poulin, Theil – Extracellular (default)

• Berezhkovskiy

• Poulin, Theil – Homogeneous

• Rodgers, Leahy, Rowland

• Lukacova

• Lukacova with Lysosomes

• User Defined

If User Defined is selected, the Calculate Tissue K_p button will not work.

f_u Extracellular Method

A drop-down. Selects the method used to calculate the fraction unbound in the extracellular compartment for permeability limited tissues.

The following methods are available:

• Kp Based (default)

• Poulin

f_u Intracellular Method

A drop-down. Selects the method used to calculate the fraction unbound in the intracellular compartment for permeability limited tissues.

The following methods are available:

• Lukacova v2 (default)

• Lukacova v2 with lysosomes

• Lukacova v1

• Poulin

Input/Option

Description

Normal Tissues

A drop-down. Selects the lipophilicity used in the Kp calculation for all tissues that are not defined as adipose (see Physiology sub-panel - Tissues).

The following methods are available:

• LogP - Octanol (default)

• LogD - Octanol

Yellow Marrow

A drop-down. Selects the lipophilicity used in the Kp calculation for Yellow Marrow. The following methods are available:

• LogP – Vegetable Oil (default)

• LogP - Octanol

• LogD - Vegetable Oil (default with Poulin’s method)

Adipose

A drop-down. Selects the lipophilicity used in the Kp calculation for all tissues that are defined as adipose (see Physiology sub-panel - Tissues).

The following methods are available:

• LogP – Vegetable Oil (default)

• LogD - Vegetable Oil (default with Poulin’s method)

LogP / D_vow

A drop-down. Selects the equation to use to convert the octanol/water partition coefficient to the vegetable oil/water partition coefficient. Vegetable oil/water distribution coefficient is then calculated by taking into consideration drug’s ionization.

The following methods are available:

• General (default)

• H-bond Donor

• H-bond Acceptor

• Base

Note: General is the equation published by Poulin ^{1 2} , Base is recommended for bases with pKa > 7 and logP > 2.

Tissue Albumin

A drop-down. Selects the albumin tissue:plasma concentration ratio values.

The following methods are available:

• Rowland ³ (default)

• Constant (uses 0.15 for Adipose and Yellow Marrow and 0.5 for all remaining tissues) (default with Poulin’s method)

• Rothschild ⁴

• Rowland Neutral (lipoprotein ratio; used for non-ionizable compounds)

GPX™

Legacy GastroPlus®

Kp Method

Poulin, Theil – Homogeneous

Poulin, Theil – Homogeneous

Poulin, Theil – Extracellular

Poulin, Theil – Extracellular

Berezhkovskiy

Berezhkovskiy

Rodgers, Leahy, Rowland

Rodgers, Leahy, Rowland

Lukacova

Lukacova (Rodgers-Single)

Lukacova with Lysosomes

Lukacova with Lysosomes

User Defined

User Defined

Fut (Perfusion Limited)

Poulin

Poulin Eq.

Lukacova v1

S+ v9.0 and earlier

Kp Based

S+ v9.5 (Default)

Fu extracellular (Permeability Limited)

Poulin

Poulin Eq.

Kp Based

S+ v9.5 (Default)

Fu intracellular (Permeability Limited)

Poulin

Poulin Eq.

Lukacova v1

S+ v9.0 and earlier

Lukacova v2 with lysosomes

S+ v9.5 w/Lys

Lukacova v2

S+ v9.5 (Default)

Input/Option

Description

Steady State Volume of Distribution (V_ss)

Estimated volume of distribution at steady state based on the settings selected for the PBPK model. The units (L, mL) can be edited using the drop-down.

Systemic Clearance (CL_sys)

Calculated systemic plasma clearance based on the sum of the systemic plasma clearance in each tissue. The units (L/h, mL/min, mL/s, L/min) can be edited using the drop-down.

Note that metabolic clearance and transporter-based elimination, as set up via the enzyme and transporter kinetics for the selected compound, will not be counted in this number.

t_½

The calculated half-life based on the V_ss and CL_sys determined above.

Kp Modifier Table

A table for each Kp modifier showing the original value, the current modifier, and the modified value. The modified value is what is used in the Kp calculations. The modified value may be capped based on physiological constraints.

• LogP/LogD — a multiplier for the LogP or LogD value, as input in the Compounds view. LogP vs LogD is determined by the selection for the compound in the Compounds view. The modifier can be negative, and there is no cap on the modified value.
  If the Lipid Adjusted f_up is selected as the f_up method at the top of the Pharmacokinetics view, this modifier is applied to LogP/LogD prior to the calculation of the Lipid Adjusted f_up during Kp calculations.

• RBP — a multiplier for the blood-to-plasma concentration ratio. Cannot be negative. The modified value is capped on the lower bound by 1 - Hematocrit.

• Fup (%) — a multiplier for the experimental fraction unbound in plasma. Cannot be negative. The modified value is capped between 0 and 100%.
  If the Lipid Adjusted f_up is selected as the f_up method at the top of the Pharmacokinetics view, this modifier is applied prior to the calculation of the Lipid Adjusted f_up during Kp calculations.

Ka_APL Source

A drop-down. Selects the source of the acidic phospholipid binding constant (Ka_APL). Options include:

• Blood Plasma Concentration Ratio: estimate the Ka_APL from Blood Plasma Concentration Ratio (RBP). Selected by default.

• Calculate From Kp: calculate the Ka_APL from a measured tissue Kp.

• User Defined: enter a user defined Ka_APL.

Ka_APL

Displays the current Ka_APL value. If the Ka_APL Source is set to Blood Plasma Concentration Ratio or Calculate from Kp, this field will be read only and display the calculated value. If the Ka_APL Source is set to User Defined, the desired value can be typed in this field.

Note that Ka_APL is only relevant for molecules with a basic pKa using the Lukacova, Lukacova with Lysosomes, or Rodgers, Leahy, Rowland Kp calculation methods.

Tissue

A drop-down. Selects which tissue to use when calculating Ka_APL from a measured tissue Kp.

Applicable only when Ka_APL Source is set to Calculate From Kp.

Tissue Kp

Number entry field for the experimentally measured tissue Kp.

Applicable only when Ka_APL Source is set to Calculate From Kp.

Observed Vss

Number entry field for the experimentally Observed Steady State Volume of Distribution (Vss). The value can be edited.

Vss

Displays the predicted Vss in L.

Fit Kp Modifiers

A button. Automatically fits the best Kp Modifiers to match the entered Observed Vss. The modifier with the combined lowest error in Vss prediction and lowest change from baseline is automatically selected.

Calculate Tissue Kp

A button. Recalculates tissue partition coefficients (Kps) for the PBPK model. This serves the same function as the Calculate Tissue Kp button in the main PBPKPlus™ panel.

Tissue Distribution Plot

A stacked bar chart showing tissue-specific Kp values and the percentage of drug binding/partitioning to each tissue component.

The specific components shown will depend on both the compound properties and the Kp calculation method selection. Note that when the Kp method is set to User Defined, the corresponding tissues will not be present in the plot.

Note that this plot updates in real-time when the Kp modifiers and/or the Ka_APL Source or value are changed, providing a preview of any adjustments in the advanced distribution settings. However, these changes will not be reflected in the model as a whole until the Calculate Tissue Kp button is clicked.