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Split CYP2D6 DDI and DDGI evaluations
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‎Qualification/Input/Content/Appendix_DDI_Implementation.md‎

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Drug-drug interaction simulations in the OSP Suite are represented through mechanistic changes in drug disposition processes. Depending on the compound and interaction scenario, these processes can include reversible enzyme inhibition, time-dependent inactivation, induction, transporter inhibition, transporter induction, or changes in multiple pathways.
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For CYP2D6 DDGI scenarios, genotype-dependent activity is represented through phenotype-specific or activity-score-specific model settings where supported by the source model. The resulting simulations compare the victim-drug exposure with and without the perpetrator under the clinical dosing schedule. AUC and Cmax ratios are then calculated from matched control and interaction simulations.
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The qualification plots compare predicted and observed exposure ratios. Performance is summarized using predicted versus observed plots, predicted/observed residual plots, geometric mean fold error, two-fold limits, and the limits proposed for ratio endpoints by Guest et al.

‎Qualification/Input/Content/Appendix_OSP_Introduction.md‎

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The Open Systems Pharmacology Suite provides a software environment for whole-body physiologically based pharmacokinetic modeling and simulation. The suite includes PK-Sim for model building and population simulation, MoBi for detailed model extension, and supporting R packages for qualification and reporting workflows.
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Models are composed of physiological system information, compound-specific parameters, formulations, administration protocols, and observed data. Simulations can be combined with observed clinical data to evaluate whether model predictions are adequate for a defined context of use.
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The qualification workflow uses versioned model snapshots and a machine-readable qualification plan to support reproducibility. The report generated from the plan documents the simulations, observed data comparisons, and summary performance metrics used to evaluate the intended use.

‎Qualification/Input/Content/Appendix_Requalification_Workflow.md‎

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The requalification workflow is driven by the qualification plan. The plan defines the model snapshots, simulations, observed datasets, output paths, comparison windows, figures, tables, and report sections.
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The workflow loads the referenced model snapshots, runs the required simulations, calculates exposure ratios and concentration-time profile comparisons, and writes a report-ready output folder. The generated report should be reviewed for scientific consistency, expected model versions, complete figures, correct study metadata, and warnings from the simulation or reporting logs.
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Before publication, the final report should be regenerated from a clean environment using the intended OSP Suite and qualification framework versions. The output should be checked against the committed qualification plan and the exact model snapshot releases used for qualification.

‎Qualification/Input/Content/Atomoxetine-Desipramine-DDI.md‎

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| **Source** | **Route** | **Schedule** | **Pop.** | **Sex** | **N** | **Perpetrator** |
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| ----------------------------- | --------- | ------------ | -------- | ------- | ----- | ------------------------ |
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| [Sauer 2004](#4-references) | po | 50 mg s.d. | American | m | 22 | +/- ATO, 60 mg b.i.d. po |
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| [Sauer 2004](#references) | po | 50 mg s.d. | American | m | 22 | +/- ATO, 60 mg b.i.d. po |
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**Table 7:**<a name="table-7"></a> ATO: atomoxetine, b.i.d.: twice daily, m: male, N: number of study participants, po: oral, pop.: population used in simulations, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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‎Qualification/Input/Content/Atomoxetine-Midazolam-DDI.md‎

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| **Source** | **Route** | **Schedule** | **Pop.** | **Sex** | **N** | **Perpetrator** |
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| ------------------------------ | --------- | ------------- | -------- | ------- | ----- | ------------------------- |
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| [Sauer 2004](#4-references) | po | 5 mg s.d. | American | f | 8 | +/- ATO, 60 mg b.i.d. po |
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| [Sauer 2004](#references) | po | 5 mg s.d. | American | f | 8 | +/- ATO, 60 mg b.i.d. po |
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**Table 7:**<a name="table-19"></a> ATO: atomoxetine, b.i.d.: twice daily, f: female, N: number of study participants, po: oral, pop.: population used in simulations, q.d.: once daily, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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**Table 19:**<a name="table-19"></a> ATO: atomoxetine, b.i.d.: twice daily, f: female, N: number of study participants, po: oral, pop.: population used in simulations, q.d.: once daily, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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‎Qualification/Input/Content/Bupropion-Atomoxetine-DDGI.md‎

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| **Source** | **Route** | **Schedule** | **Pop.** | **Sex** | **N** | **Perpetrator** |
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| ----------------------------- | --------- | ------------- | -------- | ------- | ----- | ---------------------------- |
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| [Todor 2016](#4-references) | po | 25 mg s.d. | European | m | 2 PM | +/- BUP, 150/300 mg q.d. po |
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| [Todor 2016](#4-references) | po | 25 mg s.d. | European | m | 18 NM | +/- BUP, 150/300 mg q.d. po |
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| [Todor 2016](#references) | po | 25 mg s.d. | European | m | 2 PM | +/- BUP, 150/300 mg q.d. po |
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| [Todor 2016](#references) | po | 25 mg s.d. | European | m | 18 NM | +/- BUP, 150/300 mg q.d. po |
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**Table 7:**<a name="table-2"></a> BUP: bupropion, m: male, N: number of study participants, NM: CYP2D6 normal metabolizer, PM: CYP2D6 poor metabolizer, po: oral, pop.: population used in simulations, q.d.: once daily, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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**Table 2:**<a name="table-2"></a> BUP: bupropion, m: male, N: number of study participants, NM: CYP2D6 normal metabolizer, PM: CYP2D6 poor metabolizer, po: oral, pop.: population used in simulations, q.d.: once daily, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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‎Qualification/Input/Content/Bupropion-Desipramine-DDI.md‎

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| **Source** | **Route** | **Schedule** | **Pop.** | **Sex** | **N** | **Perpetrator** |
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| ----------------------------- | --------- | ------------ | -------- | ------- | ----- | ------------------------------ |
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| [Reese 2008](#4-references) | po | 50 mg s.d. | American | m | 15 | +/- BUP, 150 mg q.d./b.i.d. po |
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| [Reese 2008](#references) | po | 50 mg s.d. | American | m | 15 | +/- BUP, 150 mg q.d./b.i.d. po |
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**Table 7:**<a name="table-8"></a> b.i.d.: twice daily, BUP: bupropion, m: male, N: number of study participants, po: oral, pop.: population used in simulations, q.d.: once daily, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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**Table 8:**<a name="table-8"></a> b.i.d.: twice daily, BUP: bupropion, m: male, N: number of study participants, po: oral, pop.: population used in simulations, q.d.: once daily, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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‎Qualification/Input/Content/Carbamazepine-Quinidine-DDI.md‎

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| **Source** | **Route** | **Schedule** | **Pop.** | **Sex** | **N** | **Perpetrator** |
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| ------------------------------ | --------- | ------------ | -------- | ------- | ----- | ---------------------------- |
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| [Andreasen 2007](#4-references)| po | 200 mg s.d. | European | m | 10 | +/- CBZ, 200/400 mg b.i.d. po|
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| [Andreasen 2007](#references)| po | 200 mg s.d. | European | m | 10 | +/- CBZ, 200/400 mg b.i.d. po|
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**Table 5:**<a name="table-22"></a> b.i.d.: twice daily, CBZ: carbamazepine, m: male, N: number of study participants, po: oral, pop.: population used in simulations, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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**Table 22:**<a name="table-22"></a> b.i.d.: twice daily, CBZ: carbamazepine, m: male, N: number of study participants, po: oral, pop.: population used in simulations, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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‎Qualification/Input/Content/Cimetidine-Metoprolol-DDI.md‎

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| **Source** | **Route** | **Schedule** | **Pop.** | **Sex** | **N** | **Perpetrator** |
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| ------------------------------------ | --------- | ------------- | -------- | ------- | ----- | ----------------------------- |
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| [Chellingsworth 1988](#4-references) | po | 100 mg s.d. | European | m | 12 | +/- CIM, 800 mg q.d. po |
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| [Chellingsworth 1988](#4-references) | po | 100 mg b.i.d. | European | m | 12 | +/- CIM, 800 mg q.d. po |
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| [Toon 1988](#4-references) | po | 100 mg b.i.d. | European | m | 12 | +/- CIM, 800 mg q.d. po |
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| [Kirch 1982](#4-references) | po | 100 mg b.i.d. | European | m | 6 | +/- CIM, 200/400 mg q.i.d. po |
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| [Chellingsworth 1988](#references) | po | 100 mg s.d. | European | m | 12 | +/- CIM, 800 mg q.d. po |
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| [Chellingsworth 1988](#references) | po | 100 mg b.i.d. | European | m | 12 | +/- CIM, 800 mg q.d. po |
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| [Toon 1988](#references) | po | 100 mg b.i.d. | European | m | 12 | +/- CIM, 800 mg q.d. po |
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| [Kirch 1982](#references) | po | 100 mg b.i.d. | European | m | 6 | +/- CIM, 200/400 mg q.i.d. po |
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**Table 7:**<a name="table-14"></a> b.i.d.: twice daily, CIM: cimetidine, m: male, N: number of study participants, po: oral, pop.: population used in simulations, q.d.: once daily, q.i.d.: four times daily, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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**Table 14:**<a name="table-14"></a> b.i.d.: twice daily, CIM: cimetidine, m: male, N: number of study participants, po: oral, pop.: population used in simulations, q.d.: once daily, q.i.d.: four times daily, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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‎Qualification/Input/Content/Cimetidine-Quinidine-DDI.md‎

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| **Source** | **Route** | **Schedule** | **Pop.** | **Sex** | **N** | **Perpetrator** |
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| ----------------------------- | --------- | ------------ | -------- | ------- | ----- | ------------------------- |
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| [Kolb 1984](#4-references) | po | 400 mg s.d. | American | m | 9 | +/- CIM, 300 mg q.d. po |
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| [Hardy 1983](#4-references) | po | 400 mg s.d. | American | m | 9 | +/- CIM, 300 mg q.i.d. po |
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**Table 6:**<a name="table-23"></a> CIM: cimetidine, m: male, N: number of study participants, po: oral, pop.: population used in simulations, q.d.: once daily, q.i.d.: four times daily, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.
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| [Kolb 1984](#references) | po | 400 mg s.d. | American | m | 9 | +/- CIM, 300 mg q.d. po |
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| [Hardy 1988](#references) | po | 400 mg s.d. | American | m | 9 | +/- CIM, 300 mg q.i.d. po |
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**Table 23:**<a name="table-23"></a> CIM: cimetidine, m: male, N: number of study participants, po: oral, pop.: population used in simulations, q.d.: once daily, q.i.d.: four times daily, s.d.: single dose. If perpetrator or victim drugs were applied in form of salts, the respective dose of base was calculated and incorporated in simulations.

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