DDI Module

Input/Option

Description

Configuration

Select the general settings of Physiology Schedule and Prediction Type, plus Simulation Mode for Dynamic simulations.

Victims

Define compounds whose exposure may be impacted by co-administered drugs

Perpetrators

Define compounds that may impact exposure of co-administered drugs

Perpetrator Steady-State Concentration

Define effective perpetrator concentrations to use in Steady State predictions (enabled only when Steady State Prediction Type is selected in the Configuration panel).

Population Settings

Define the population of virtual subjects to be used in the population simulation (enabled only when Dynamic Prediction Type and Population Simulation Mode is selected in the Configuration panel and after Victim and Perpetrator compounds were defined in their respective panels).

Run

Execute DDI predictions.

Results

View the predicted DDI results.

Input/Option

Description

Physiology Schedule

Select the Physiology Schedule to use in the DDI predictions.

Prediction Type

Select Dynamic or Steady State prediction.

Simulation Mode

Select to use Single Simulation or Population Simulation (enabled and applicable only with Dynamic Prediction Type).

Input/Option

Description

Show Only Relevant Compounds

Turn ON this toggle (it will turn green) to display only those compounds in the current project which have a potential for interaction with the selected Perpetrator compounds (i.e. substrates of the enzymes and transporters which are inhibited or induced by the selected Perpetrator). All compounds in the current project will be displayed if no Perpetrator compounds are selected yet.

Parent Victims

Table of compounds in the current project that are potential victims in DDI. The list is dependent on the selections in the Configurations panel and whether the Show Only Relevant Compounds toggle is ON. When Dynamic Prediction Type is selected in the Configuration panel, the table will include only compounds that are linked to simulations with the same Pharmacokinetic Model type (Compartmental or PBPK) as defined in the Physiology Schedule selected in the Configuration Panel.

The table includes up to four columns:

• Compound – Compound name.

• Select – Turn ON the toggle to include the compound in the DDI simulation as a potential victim compound.

• Simulation – List of relevant simulations for each compound. Click on the drop-down selector to select a specific simulation for the given compound (active only for compounds selected in the Select column).

• Fraction Metabolized Source –Select the source of f_m values for the corresponding Victim compound that will be displayed in the Victim Metabolism and Transport Details panel and used in Steady State DDI predictions. The options include: Enzyme Kinetics – the f_m values are estimated from the information in the Enzyme Table for the given compound and the Physiology Schedule selected in the Configuration Panel; In Vitro – estimated from in vitro assays, selecting this option enables In Vitro Fraction Metabolized Calculator sub-panel; User – allows manual entry of Fm values; Predicted (AP) – uses f_m values predicted by ADMET Predictor® during structure import. The column is visible and applicable only with Steady State Prediction Type, the drop-down is active only for compounds selected in the Select column.

Victim Dosing and Pharmacokinetic Information for Steady-State DDI

Table summarizing the Dosing and Pharmacokinetic information of compounds selected in the Parent Victims table (applicable and enabled only with Steady State Prediction Type).

• F_a – fraction absorbed, is used to obtain F_g.

• FD_p – fraction of dose entering portal vein, is used to obtain F_g.

• F_g – fraction of dose escaping intestinal metabolism. Calculated as ratio of the FD_p and F_a values and is used in steady-state predictions to account for the effect of enzyme inhibition in the gut.

• f_{Other Sys CL} - contribution of other clearance (not affected by the investigated enzymes) to total Systemic clearance.

• f_{Other Gut CL} - contribution of other clearance (not affected by the investigated enzymes) to total Gut clearance.

• Dose (mg) – Dose of the victim compound. The units and the value can be edited (mg, µg, g).

• Administration Time (h) – Time of the victim compound administration relative to the first dose of perpetrator. The time impacts the estimate of the simulated perpetrator concentrations. The units and the value can be edited (h, s, min, d).

In Vitro Fraction Metabolized Calculator

Built-in tool for estimation of the in vivo f_m values for steady-state DDI predictions from in vitro assays (in recombinant enzymes or liver microsomes). Enabled when Prediction Type in the Configuration panel is set to Steady State Prediction and the Fraction Metabolized Source for the selected Parent Victim compound is set to InVitro.

Victim Metabolism Transport Details

Sub-panel summarizing f_m values for victim compounds selected for the DDI prediction. Enabled and functional when Prediction Type in the Configuration panel is set to Steady State Prediction. To view f_m for Dynamic Simulations, switch to Steady State to enable the calculations and then back to Dynamic to complete the simulation set up.

Input/Option

Description

Victim Compound

Select the compound to calculate the f_m values. The drop-down includes the list of compounds which were selected in the Parent Victims table and their Fraction Metabolized Source was set to InVitro.

Fraction Metabolized Type

Select the type of in vitro assay (HLM for human liver microsomes or rCYP for recombinant CYP enzyme systems) that was used to determine the compound’s metabolic profile.

Population

Select the population (American, Chinese, or Japanese) to define the average in vivo CYP expression levels in liver.

Liver Weight

Liver weight – one of the conversion factors for extrapolation of in vitro clearance to intrinsic in vivo clearance. Default value is 1500 g.

Microsomal Protein

Amount of microsomal protein per gram liver – a conversion factor for extrapolation of in vitro clearance to intrinsic in vivo clearance. Default value is 38 mg/g.

% Non-CYP CL

Enter the percent of a compound’s systemic clearance (if any) due to mechanisms other than CYP metabolism.

CL-int Uninhibited

Enter in vitro intrinsic clearance measured in HLM without the presence of any inhibitors (enabled only when HLM is selected for Fraction Metabolized Type).

Enter InVitro CL-int For Standard To Calculate ISEFS

Turn this toggle ON to enable entries of standard compounds measured in different rCYP systems and calculate ISEFs (intersystem extrapolation factors). Turn the toggle OFF for direct entry of ISEF values. (Toggle is enabled only when rCYP is selected for Fraction Metabolized Type).

Table for Clearance entries

In vitro measurements reflecting the compound’s metabolism by different CYP enzymes that will be used to calculate f_m values:

• Enzyme – CYP enzyme.

• CYP Expression (pmol/mg) – average CYP expression in the selected Population. Default values are populated based on the selected Population. The values can be modified to reflect a specific subpopulation group if desired.

• CYP Expression CV (%) – Average CYP expression variability in the selected Population.

• Compound CLint rCYP ((µL/min)/pmol)– Enter in vitro clearance measured in recombinant system for the specific CYP enzyme and select appropriate units (column visible only when rCYP is selected for Fraction Metabolized Type).

• Compound CLint HLM ((µL/min)/mg)– Enter in vitro clearance measured in liver microsomes in the presence of specific inhibitor of given CYP enzyme and select appropriate units (column visible only when HLM is selected for Fraction Metabolized Type).

• Micros CYP expr – enter expression level of given CYP enzyme in the microsomal preparation used in the in vitro assay (column enabled when HLM is selected for Fraction Metabolized Type, or when rCYP is selected for Fraction Metabolized Type and Enter InVitro CL-int For Standard to Calculate ISEFs toggle is ON).

• Standard CLint rCYP ((µL/min)/pmol)– enter in vitro intrinsic clearance of prototypical substrate of given CYP enzyme measured in the same recombinant CYP system as the test compound and select relevant units (column visible only when rCYP is selected for Fraction Metabolized Type and enabled when Enter InVitro CL-int For Standard to Calculate ISEFs toggle is ON).

• Standard CLint HLM ((µL/min)/mg)– enter in vitro intrinsic clearance of prototypical substrate of given CYP enzyme measured in HLM system and select relevant units (column visible only when rCYP is selected for Fraction Metabolized Type and enabled when Enter InVitro CL-int For Standard to Calculate ISEFs toggle is ON).

• ISEF – intersystem extrapolation factor reflecting activity of given CYP enzyme in rCYP system used in the in vitro assay. The column is disabled and values are calculated from entries in Micros CYP expr, Standard CLint rCYP, and Standard CLint HLM columns when Enter InVitro CL-int For Standard to Calculate ISEFs toggle is ON. The column is enabled and requires user entry of ISEF values when Enter InVitro CL-int For Standard to Calculate ISEFs toggle is OFF (column visible only when rCYP is selected for Fraction Metabolized Type).

• Compound CL,u in vivo (L/h)– calculated unbound in vivo liver clearance due to the given CYP enzyme estimated from the corresponding in vitro measurements.

• fm(%) – calculated percent contribution of given enzyme to compound’s systemic clearance calculated from Compound CL,u in vivo values and % Non-CYP CL.

Calculate fm Values

After entering all in vitro measurements in the table, click this button to calculate f_m values for CYP enzymes involved in the selected compound’s elimination. The calculated fm values are automatically exported into the Victim Metabolism Transport Details panel.

Input/Option

Description

Victim Metabolism Transport Parameters

Table summarizing f_m values and their sources for compounds selected in the Parent Victims table:

• Compound – compound name.

• Enz/Trans – enzyme or transporter name.

• Location – enzyme or transporter location.

• CL_int (L/h)– intrinsic clearance due to the corresponding enzyme.

• f_m – fraction of clearance contributed by the corresponding enzyme.

• f_m source – source of f_m value in the table (Enzyme Kinetics – values are estimated from the information in the Enzyme Table for the given compound and the Physiology Schedule selected in the Configuration Panel; In Vitro – values estimated from in vitro assays using In vitro Fraction Metabolized Calculator panel; User –manually entered values; Predicted (AP) –values predicted by ADMET Predictor® during structure import).

• Turnover (1/min)– k_deg value for the given enzyme/transporter used in DDI predictions involving time-dependent inhibition or induction.

User Defined Fm Compounds

A drop-down containing list of compounds selected in the Parent Victims table for which the Fraction Metabolized Source was set to User (enabled only when at least one selected Parent Victim has Fraction Metabolized Source set to User). Select compound for which a new entry needs to be added to the Victim Metabolism Transport Parameters table.

Add | Delete

Add or Delete an entry from the table. Clicking Add button will add an entry for the compound selected in the User Defined Fm Compounds drop-down.

Note: To delete an entry, select the row by holding the Ctrl key and clicking one cell in the row and then click the Delete button. These buttons are enabled only when User is selected as Fraction Metabolized Source of Parent Victims table for at least one of the selected compounds.

Metabolic Profile in Liver/Gut

Plots of metabolic profiles in Liver and Gut for the compound selected in the Victim Metabolism Transport Parameters table (use Ctrl + click to select the row for the desired compound).

Input/Option

Description

Show Only Relevant Perpetrators

Turn ON this toggle to display only those compounds in the current project which have a potential for interaction with the selected Victim compounds (i.e. display compounds that inhibit or induce the enzymes and transporters that impact exposure of the selected victim compounds). All compounds in the current project will be displayed if no Victim compounds are selected yet.

Automated Fu Correction

A toggle. When turned on, it will automatically convert interaction parameter values (Ki, IC50, EC50) between the total and unbound to match the selected perpetrator concentration type. The conversion requires a defined in vitro fraction unbound in the Perpetration Parameters table.

Parent Perpetrators

Table of compounds in the current project that are potential perpetrators in the DDI. The list is dependent on the selections in the Configurations panel and whether the Show Only Relevant Compounds toggle is ON. When Dynamic Prediction Type is selected in the Configuration Panel, the table will include only compounds that are linked to simulations with the same Pharmacokinetic Model type (Compartmental or PBPK) as defined in the Physiology Schedule selected in the Configuration Panel.

The table includes three columns:

• Compound – Compound name.

• Simulation – List of relevant simulations for each compound. Click on the drop-down to select a specific simulation for the given compound (active only for compounds selected in the Select column).

• Select – Turn ON the toggle to include the compound in the DDI simulation as potential perpetrator compound.

Perpetrator Dosing and Pharmacokinetic Information

Table summarizing the Dosing and Pharmacokinetic information of compounds selected in the Parent Perpetrators table. These values are used to provide estimates of Calculated Perpetrator concentrations in Steady State DDI predictions.

• Compound – Compound name.

• Dose (mg)– Dose (given by the Dosing Schedule of the simulation selected for the corresponding compound in the Parent Perpetrators table). This value can be edited.

• Interval – Dosing interval. This value can be edited.

• CL (L/h)– Total systemic clearance.

• k_a (1/min)– first order absorption rate constant.

• k_el (1/min)– elimination rate constant.

• Q_e (L/h)– enterocytic blood flow. This value can be edited.

• Q_h (L/h)– liver blood flow. This value can be edited.

• F_up – fraction unbound in plasma. This value can be edited.

• F_a – fraction absorbed.

• FD_p – fraction of dose entering portal vein.

• F – fraction bioavailable.

Fa, FDp and F all have to be entered in the Observed Data view, Parameters sub-panel, and the series must be linked in the Simulation view, Compound Settings panel, Observed Data sub-panel, of the relevant simulation. See Parameters Panel and Observed Data sub-panel for more details.

Perpetration Parameters

Table summarizing interaction parameters for perpetrators used in the DDI prediction (applicable with both Steady State and Dynamic predictions).

• Compound – Compound name (parent compound and/or it’s metabolite).

• Protein – Enzyme or transporter name.

• Action – type of interaction (inhibition or induction)

• Ki/IC50/EC50 – type of parameter value (select Ki or IC50 for inhibition and EC50 for induction).

• Type – interaction type (Time Dependent or Competitive).

• Vitro/Vivo – how the interaction parameter was determined (in vitro or in vivo).

• U/T – specifies whether the interaction parameter represents unbound or total value.

• Value – value for the selected interaction parameter (Ki, IC50, or EC50).

• Select – turn the toggle ON to use the parameter value in the DDI prediction (only one value may be selected for a specific interaction, i.e. compound/protein/action/type combination).

• k_inact (1/min)– inactivation rate constant (relevant and enabled only when time dependent inhibition is selected).

• E_max – maximum induction rate (relevant and enabled only when induction is selected).

• Validated? – information on whether the value was validated for the DDI prediction (select Yes or No to keep track of the parameter values that were validated).

• Self? – information on whether the interaction is important to correctly capture the perpetrator’s own exposure due to autoinduction or autoinhibition (select Yes or No to keep track of important selections for perpetrator and make sure to always turn ON the toggle in the Select column when the value in this column is Yes).

• In Vitro f_u – compound fraction unbound in the measurement environment (value is used to convert between total and unbound Ki/IC50/EC50 values to match the selected Perpetrator Concentration type).

• In Vitro f_u Type – Select the source of In Vitro fu value (User Defined for manual entry when the In Vitro f_u value has been measured or select a method to estimate the value from the compound’s properties).

• IPConc (mg/mL)– Concentration of protein in the in vitro assay (entry is used to estimate In Vitro fu when Austin or Hallifax is selected in the In Vitro f_u Type column).

• Substrate – Information on which substrate was used in the in vitro assay determining the Perpetration parameter value (this entry is for information only).

• Reference – Information on the source of the Perpetration parameter value.

Add / Delete

Add or Delete entries from the table.

Note: To delete an entry, select the row by holding the Ctrl key and clicking one cell in the row and then click the Delete button.

Input/Option

Description

Calculated Steady State Concentrations

Effective perpetrator concentrations are estimated from information in the Perpetrator Dosing and Pharmacokinetic Information table using standard formulas for average, peak (C_max) and trough (C_min) plasma concentrations in the steady state, average and peak (C_max) liver inlet concentrations, or drug concentration in the gut. Refer to Scientific Principles Guide or Equations Guide for the details of the equations.

Simulated Concentrations

Selecting any of the Simulated Concentrations will cause the program to run a simulation for the perpetrator based on the information in the Perpetrator Dosing and Pharmacokinetics Information table and the settings for the Simulation selected for given perpetrator in Parent Perpetrators table. The perpetrator concentration to be used in the steady-state equation is then obtained from the simulated perpetrator concentration in plasma or liver (depending on the selection) and in the gut (if at least one of the victim’s metabolizing enzymes is located in gut). Refer to Scientific Principles Guide for details.

User Specified Effective Perpetrator Concentrations

The User Specified Effective Perpetrator Concentrations will create an entry in the Perpetrator Steady-State Concentrations table in the Results section of the DDI window where you can manually enter the expected effective perpetrator concentration in the gut or liver.

*** Keep in mind that, unlike Calculated or Simulated Perpetrator concentrations, these User Specified Effective Perpetrator Concentrations are fixed numbers. The program will not scale them for a different perpetrator dose or dosing interval. It is user’s responsibility to ensure that the value corresponds to the intended dosing of the perpetrator.

Automatically select corresponding gut concentration

When the Automatically select corresponding gut concentration toggle is turned ON, the steady-state DDI predictions will be calculated by combining total systemic with total gut and unbound systemic with unbound gut concentrations within each section (using ‘calculated’ gut concentration with ‘calculated’ plasma or liver concentration and ‘simulated’ gut concentration with ‘simulated’ plasma or liver concentration). Otherwise, the module will produce steady-state predictions for all combinations of the selected systemic/liver and gut concentrations.

Input/Option

Description

Species

Simulations species (dependent on the Physiology Schedule selected in the Configuration panel).

Ethnicity

Population to sample from (current options include American, Japanese, Chinese).

Health Status

Health status for the generated virtual subjects (healthy, pregnant, different degrees of hepatic or renal impairment).

Population Size

Number of virtual subjects to be created for each virtual population.

Repeated Trial Size

Number of virtual populations to be created.

Population Type

Parameter sampling strategy (PEAR – account for parameter covariates where applicable, applicable only with PBPK model, Monte Carlo – ignore parameter covariates and sample each parameter independently from its own distribution).

Update Partition Coefficients (K_p)

A toggle. Turn on to update K_ps for each virtual subject based on the parameter values selected for each subject and selected K_p method for the compound.

Intrasubject Variability Settings

Section where intrasubject variability is set up.

Physiological Intrasubject Variability

A toggle. Controls whether additional variability will be applied to gut physiological parameters (transit times, intestinal fluid volume, pH values, and bile salt concentrations for each gut section) in the same subject between simulations.

Synchronization Preferences

Synchronize parameter values related to the compound and/or protein (enzyme or transporter).

• Compound – A drop-down. Selects the compound or protein (enzyme or transporter) for which the selected synchronization applies.

• Synchronize Liver FPE and General Clearance – A toggle. Turn on for a compartmental PK model to update Liver FPE based on sampled General Clearance for each virtual subject (applies to selected compound).

• Synchronize V_max values across locations – A toggle. Turn on to synchronize V_max values in gut and systemic locations for the selected enzyme/transporter for each virtual subject.

• Synchronize K_m values across locations – A toggle. Turn on to use the same K_m values for the selected enzyme/transporter for each virtual subject.

• Synchronize V_max/K_m ratios – A toggle. Turn on to keep the same V_max/K_m ratio as in the baseline simulations for the selected enzyme/transporter for each virtual subject.

Individual Parameter settings

• Set Default Parameters – click the button to update all parameter values in the settings table below to the default values.

• Parameter Selector – select parameter to be varied for each virtual subject created for the population simulation. By default, most of the parameters from the base simulation will be included.

• Parameter Summary table – summary of selected parameters and their settings: Lower bound – minimum allowed value for the parameter (calculated automatically from Baseline, Std Dev, and Bounds Factor); Baseline – parameter value from the baseline simulation; Upper bound – maximum allowed value for the parameter (calculated automatically from Baseline, Std Dev, and Bounds Factor); CV% - % coefficient of variation for selected parameter (automatically updated if Std Dev value is changed); Std Dev – standard deviation for selected parameter (automatically updated if CV% is changed); Bounds Factor – defines the range of values (in terms of number of standard deviations) to sample from (i.e. value of 3 means the Lower and Upper Bound for the parameter is 3 standard deviations from the Baseline value); Distribution – sampling distribution type for the selected parameter. Regimen Scaling - A toggle that indicates gut physiological parameters (transit times, intestinal fluid volume, pH values, and bile salt concentrations for each gut section) that will be scaled in the second period, according to equation X.

Input/Option

Description

Male Fraction

% of males in the population.

Body Weight Limit Type

Define the range of body weights for virtual subjects as absolute values in kg (Absolute) or as percent of the typical value for given subject (Percent). Percent selection is recommended for pediatric populations.

Population Specification Table

Define range of demographic parameters (Age, Body Mass, or BMI) for virtual subjects included in the population simulation. Body Mass can be defined in kg or as % of typical body mass depending on selection in Body Weight Limit Type drop-down. Height is automatically calculated from Body Mass and BMI sampled for each virtual subject. Physiology column displays values from the physiology in the Physiology Schedule selected in the Configuration Panel. Enter the desired Lower Bound and Upper Bound for each parameter in their respective columns.

Enzyme Phenotype Frequency

Define the proportion of subjects with different enzyme activities to be included in the virtual population. The table is enabled if the baseline model in the simulation includes enzymes with known polymorphism in their activity.

Input/Option

Description

Check Warnings

Click this button to verify the DDI prediction settings and identify any errors that need to be addressed for accurate predictions. Any error messages will be displayed in the Message Center at the top of the interface.

Steady-State Prediction

Predict DDI using Steady-State equation (enabled only when Steady State Prediction Type is selected in the Configuration panel).

Dynamic Baseline Simulation

Complete a baseline simulation, i.e. simulation without any DDI impact (enabled only when Dynamic Single Simulation type is selected in the Configuration panel).

Dynamic Full Simulation

Complete a full dynamic simulation, i.e. simulation accounting for DDIs based on the parameters selected in the Perpetration Parameters table (enabled only when Dynamic Single Simulation type is selected in the Configuration panel).

Run Population Simulation

Complete a dynamic DDI prediction for a virtual population of subjects as defined in the Population Settings panel. The Population Simulation run automatically executes Baseline and Full simulation for each virtual subject. (enabled only when Dynamic Population Simulation type is selected in the Configuration panel).

Input/Option

Description

Perpetrator Steady-State Concentrations

Summary of effective perpetrator concentrations selected in the Perpetrator Steady-State Concentrations sub-panel:

• Compound – selected perpetrator compound (multiple perpetrators may be selected).

• Type – concentration type.

• Concentration (µg/mL)– concentration value for each type.

• Selected – turn the toggle ON/OFF to use/not use the selected value in the DDI prediction.

Steady-State AUC Ratios

Summary of AUC ratios predicted using the selected perpetrator concentrations.

• Compound – selected victim compound (multiple victim compounds may be selected).

• Type – combination of perpetrator concentrations used for the DDI prediction.

• AUC Ratio Gut – predicted contribution of gut to the DDI.

• AUC Ratio Liver – predicted contribution of liver to the DDI.

• AUC Ratio Total – predicted total DDI (gut contribution x liver contribution).

• Classification – perpetrator classification based on predicted AUC ratio: weak – AUC ratio in range 1.25-2; moderate – AUC ratio in range 2-5; strong – AUC ratio more than 5).

Input/Option

Description

Dynamic DDI Calculated Outputs

Standard simulation endpoints from Baseline and Full Dynamic simulations for all compounds included in the dynamic DDI prediction:

• F_a – fraction absorbed.

• FD_p – fraction of dose entering portal vein.

• F – fraction bioavailable.

• C_max (µg/mL)– maximum plasma concentration.

• T_max (h)– time to maximum plasma concentration.

• AUC_inf ((ng/mL).h)– area under the concentration-time curve extrapolated to infinity.

• AUC_t ((ng/mL).h)– area under the concentration time curve across the simulation time.

In Population Simulation Mode, the values represent the average across all virtual subjects.

Note: With multiple doses, the values represent the entire course of simulation.

Dynamic DDI Ratios

Ratios of all simulation endpoints calculated as Full Dynamic Simulation/Baseline Simulation.

In Population Simulation Mode, the values represent ratios of average values reported in the Dynamic DDI Calculated Outputs table.

Compound

Select compound to display statistics for simulated PK endpoints. Displayed only with the Population Simulation Mode.

Statistics Table

Summary statistics for simulated PK endpoints for compound selected in the drop-down above.

• PK Parameter – PK endpoint and simulation (DDI – full dynamic simulation, baseline – baseline simulation without DDI, ratio – statistics for individual DDI/baseline ratios).

• Mean – arithmetic mean.

• CV – variance.

• Min – minimum value.

• Max – maximum value.

• Geom Mean – geometric mean.

• 90% CI Lower – lower bound of 90% confidence interval calculated from raw (untransformed) data.

• 90% CI Upper – upper bound of 90% confidence interval calculated from raw (untransformed) data.

• 90% CI Ln Lower – lower bound of 90% confidence interval calculated from ln-transformed data.

• 90% CI Ln Upper – upper bound of 90% confidence interval calculated from ln-transformed data.

Displayed only with the Population Simulation Mode.