Qualification Plan Release version 2.2

This release contains the qualification plan (qualification_plan.json) including references to respective model snapshots and static content (e.g. text blocks, *.md files) to produce a qualification report evaluating the ability to perform simulations with the intended purpose to predict cytochrome P450 3A4 (CYP3A4)-mediated drug-drug interactions (DDI) of the PBPK platform PK-Sim (as part of the Open Systems Pharmacology (OSP) Suite).

The latest release of the qualification report can be found here.

Major updates

📋 High-Level Summary

This release integrates the latest Verapamil model (version 2.2) into the CYP3A4 Drug-Drug Interaction (DDI) qualification network. This update brings major enhancements to the simulation structure by incorporating Verapamil enantiomers and metabolites, expands the clinical dataset with new observed studies and dosing regimens, and updates multiple linked model snapshots across the qualification plan.

📦 Component & Model Version Updates

Several submodule snapshots and dependencies have been bumped to their latest versions to reflect the updated modeling approach and new data:

• Verapamil Model: Updated from v1.2 to v2.2
• Observed Data Database: Updated from v1.8 to v1.9
• Cimetidine-Verapamil-DDI: Updated from v1.2 to v2.0
• Rifampicin-Verapamil-DDI: Updated from v1.1 to v2.0
• Verapamil-Midazolam-DDI: Updated from v1.3 to v2.0

🧬 Pharmacokinetic & Simulation Architecture Enhancements

• Enantiomer and Metabolite Support: The generic "Verapamil" compound building block in the simulation plans has been extensively replaced with its specific enantiomers and metabolites: R-Norverapamil, S-Norverapamil, R-Verapamil, and S-Verapamil.
• Formulation Specificity: Upgraded the formulation mapping in the Verapamil-Midazolam DDI from a generic "controlled release" to the specific "Retard Tablet Verapamil (Knoll)".
• Enzyme & Transporter Updates: For the Rifampicin-Verapamil DDI, the substrate characteristics were refined. CYP2C8 was removed from the primary list, and P-gp is now fully recognized without the previous caveat stating it wasn't considered by the model.

📊 Clinical Data & Reference Additions

The validation network has been significantly expanded, particularly for the Cimetidine-Verapamil interaction.

• Expanded the evaluation from a single clinical DDI study to four clinical DDI studies evaluating seven different dosing regimens.
• New Studies Added:
  • Abernethy 1985 (Verapamil IV and PO scenarios)
  • Mikus 1990 (Verapamil PO, capturing specific R-verapamil and S-verapamil interactions)
  • Wing 1985 (Verapamil IV and PO scenarios)
• New References: Added citations and PubMed links for Abernethy 1985, Mikus 1990, and Wing 1985 to the References.md document.

⚙️ Qualification Plan Updates (qualification_plan.json)

The core JSON plan experienced major refactoring to handle the new parameters and studies:

• Added detailed output mappings, definitions, and plot configurations (time limits, colors, markers) for Abernethy 1985, Mikus 1990, Wing 1985, and Smith 1984.
• Re-mapped target outputs from generic Verapamil to Sum-Verapamil or specific enantiomers (R-Verapamil, S-Verapamil) based on the new model structure.
• Standardized naming conventions for target simulations (e.g., changing from DDI Control - Midazolam - Backman 1994 to structured, descriptive names like DDI_Verapamil-Midazolam 15 mg po, Control, Backman 1994, n=9).
• Extensively updated DDIRatio parameters to reference the specific new control/treatment simulations and their precise start times.

Minor updates

• Cimetidine-Carbamazepine-DDI: Updated from v1.1 to v1.2

Full Changelog: v2.1...v2.2