Align risperidone evaluation repo with QC-ready report structure

.github/workflows/Check_utf8.yml

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+name: Check if all required files are UTF-8
+
+on: 
+  [push, pull_request]
+
+permissions:
+  contents: read
+
+jobs:
+  utf8check:
+    uses: Open-Systems-Pharmacology/Workflows/.github/workflows/UTF8Check.yml@5e78d9c26dd9b1fd131ce69da7532dd5f82a8801
+    with:
+      file-extensions: 'R\|json\|md'  #File extension(s) to check separated by \| Examples:
+                                      #R
+                                      #R\|json

.github/workflows/CrossRefCheckWithAnchors.yml

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+name: CrossRefCheck with Anchors
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+on: 
+  push:
+    branches:
+      - review
+
+permissions:
+  contents: read
+
+jobs:
+  crossref-check-with-anchors:
+    uses: Open-Systems-Pharmacology/Workflows/.github/workflows/MarkdownCrossrefCheck_withAnchors.yml@5e78d9c26dd9b1fd131ce69da7532dd5f82a8801
+    with:
+      folder-path: 'Evaluation/report'

.github/workflows/MarkdownLinksCheck.yml

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+name: Check Markdown links
+
+on: 
+  push:
+    branches:
+      - review
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+permissions:
+  contents: read
+
+jobs:
+  markdown-link-check:
+    uses: Open-Systems-Pharmacology/Workflows/.github/workflows/MarkdownLinksCheck.yml@5e78d9c26dd9b1fd131ce69da7532dd5f82a8801
+    with:
+      folder-path: 'Evaluation/report'

.github/workflows/SpellChecker.yml

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+name: Spellcheck
+
+on: 
+  [push, pull_request]
+
+permissions:
+  contents: read
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+jobs:
+  Spellcheck:
+    uses: Open-Systems-Pharmacology/Workflows/.github/workflows/SpellChecker.yml@5e78d9c26dd9b1fd131ce69da7532dd5f82a8801

.github/workflows/ValidateEvaluationPlan.yml

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+name: Validate Evaluation Plan
+
+on: 
+  [push, pull_request]
+
+permissions:
+  contents: read
+
+jobs:
+  Validate-Evaluation-Plan:
+    uses: Open-Systems-Pharmacology/Workflows/.github/workflows/ValidateQualificationPlan.yml@5e78d9c26dd9b1fd131ce69da7532dd5f82a8801
+    with:
+      qualification-plan: 'Evaluation/Input/evaluation_plan.json'

.github/workflows/wordlist.txt

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+Abad
+Abad-Santos
+Armodafinil
+Atomoxetine
+AUClast
+Baumann
+Bertschy
+Block
+Bond
+Bondolfi
+Boonleang
+Boulton
+Clin
+Cmax
+CYP2D6
+CYP3A
+CYP3A4
+Darwish
+DeVane
+DGI
+Eap
+Edginton
+Eissing
+Feick
+Fuhr
+Gallego
+Gallego-Sadín
+GFR
+GMFE
+GOF
+Hellriegel
+Hempel
+Höhn
+Hydroxyrisperidone
+Igel
+Investig
+JCP
+Kaneo
+Kerb
+Kim
+Kneller
+Kuepfer
+Lehr
+Lippert
+Liu
+Loer
+López
+López-Rodríguez
+Mahatthanatrakul
+Markowitz
+Marok
+Mürdter
+Nakagami
+Nontaput
+Novalbos
+Ochoa
+Ontogeny
+OSP
+OSPy
+P-glycoprotein
+P-gp
+paliperidone
+Park
+Paroxetine
+PBPK
+Pharm
+Pharmacodyn
+Pharmacokinet
+Pharmacokinetic
+Pharmacokinetics
+Pharmacol
+Pharmaceutics
+Pharmacometrics
+Pharmacopsychiatry
+Pipatrattanaseree
+PK
+PK-Sim
+Psychopharmacol
+Ridtitid
+Rifampin
+Risch
+Risperidone
+Robertson
+Rodríguez
+Román
+Rüdesheim
+Rujimamahasan
+Sadín
+Saito
+Schlender
+Schmitt
+Schwab
+Selzer
+Sevestre
+Shin
+Solodenko
+Sriwiriyajan
+Sunbhanich
+Syst
+Tateishi
+Teutonico
+Ther
+Vermeulen
+Willmann
+Wongnawa
+Yang
+Yasui
+Yasui-Furukori
+Zullino
+active-moiety
+activity-score
+analyte
+analytes
+antipsychotic
+drug-gene
+drug-drug-gene
+extensive-metabolizer
+first-pass
+goodness-of-fit
+hydroxyrisperidone
+interacting-drug
+kcat
+metabolizers
+model-building
+model-verification
+multi-dose
+multiple-dose
+olanzapine
+overpredicting
+parent-metabolite
+parent-to-metabolite
+physicochemical
+poor-metabolizer
+population-level
+risperidone
+single-analyte
+single-dose
+whole-body
+HLH
+FZ
+reoptimization
+ee

.gitignore

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+Evaluation/workflow_patched.R
+justfile

Evaluation/Input/Content/Concentration_time_profiles.md

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+Simulated versus observed concentration-time profiles of all data listed in Section 2.2.2 (Clinical data) are presented below.

Evaluation/Input/Content/GOF_diagnostics.md

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+Below you find the goodness-of-fit visual diagnostic plots for PBPK model performance of all data used, as presented in Section 2.2.2 (Clinical data).
+
+The first plot shows observed versus simulated plasma concentration, the second weighted residuals versus time.

Evaluation/Input/Content/GOF_diagnostics_9hydroxyrisperidone.md

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+Below you find the goodness-of-fit visual diagnostic plots for 9-hydroxyrisperidone plasma concentration data used in the model evaluation.
+
+The first plot shows observed versus simulated plasma concentration, the second weighted residuals versus time.

Evaluation/Input/Content/GOF_diagnostics_risperidone.md

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+Below you find the goodness-of-fit visual diagnostic plots for risperidone plasma concentration data used in the model evaluation.
+
+The first plot shows observed versus simulated plasma concentration, the second weighted residuals versus time.

Evaluation/Input/Content/Input_table.md

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+The compound parameter values of the final PBPK model are illustrated below.

Evaluation/Input/Content/References.md

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+1. Rüdesheim S, Selzer D, Mürdter T, Igel S, Kerb R, Schwab M, Lehr T. Physiologically Based Pharmacokinetic Modeling to Describe the CYP2D6 Activity Score-Dependent Metabolism of Paroxetine, Atomoxetine and Risperidone. Pharmaceutics. 2022;14:1734. doi:10.3390/pharmaceutics14081734.
+2. Rüdesheim S, Loer HLH, Feick D, Marok FZ, Fuhr LM, Selzer D, et al. A Comprehensive CYP2D6 Drug-Drug-Gene Interaction Network for Application in Precision Dosing and Drug Development. Clin Pharmacol Ther. 2025.
+3. Kneller LA, Abad-Santos F, Hempel G. Physiologically Based Pharmacokinetic Modelling to Describe the Pharmacokinetics of Risperidone and 9-Hydroxyrisperidone According to Cytochrome P450 2D6 Phenotypes. Clin Pharmacokinet. 2020;59:51-65. doi:10.1007/s40262-019-00793-x.
+4. Novalbos J, López-Rodríguez R, Román M, Gallego-Sadín S, Ochoa D, Abad-Santos F. Effects of CYP2D6 genotype on the pharmacokinetics, pharmacodynamics, and safety of risperidone in healthy volunteers. J Clin Psychopharmacol. 2010;30:504-511. doi:10.1097/JCP.0b013e3181ee84c7.
+5. Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Baumann P. The effect of fluoxetine on the pharmacokinetics and safety of risperidone in psychotic patients. Pharmacopsychiatry. 2002;35:50-56. doi:10.1055/s-2002-25026.
+6. Markowitz JS, DeVane CL, Liston HL, Boulton DW, Risch SC. The effects of probenecid on the disposition of risperidone and olanzapine in healthy volunteers. Clin Pharmacol Ther. 2002;71:30-38. doi:10.1067/mcp.2002.119815.
+7. Darwish M, Bond M, Yang R, Hellriegel ET, Robertson P. Evaluation of Potential Pharmacokinetic Drug-Drug Interaction Between Armodafinil and Risperidone in Healthy Adults. Clin Drug Investig. 2015;35:725-733. doi:10.1007/s40261-015-0330-6.
+8. Mahatthanatrakul W, Sriwiriyajan S, Ridtitid W, Boonleang J, Wongnawa M, Rujimamahasan N, Pipatrattanaseree W. Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers. J Clin Pharm Ther. 2012;37:221-225. doi:10.1111/j.1365-2710.2011.01271.x.
+9. Nakagami T, Yasui-Furukori N, Saito M, Tateishi T, Kaneo S. Effect of verapamil on pharmacokinetics and pharmacodynamics of risperidone. Clin Pharmacol Ther. 2005;78:43-51. doi:10.1016/j.clpt.2005.03.009.
+10. Kim KA, Park PW, Liu KH, Kim KB, Kim HJ, Shin JG, Park JY. Effect of rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics of risperidone. J Clin Pharmacol. 2008;48:66-72. doi:10.1177/0091270007309888.
+11. Mahatthanatrakul W, Nontaput T, Ridtitid W, Wongnawa M, Sunbhanich M. Rifampin decreases plasma concentrations of risperidone in healthy volunteers. J Clin Pharm Ther. 2007;32:161-167. doi:10.1111/j.1365-2710.2007.00811.x.
+
+12. Kuepfer L, Niederalt C, Wendl T, Schlender JF, Willmann S, Lippert J, Block M, Eissing T, Teutonico D. Applied Concepts in PBPK Modeling: How to Build a PBPK/PD Model. CPT Pharmacometrics Syst Pharmacol. 2016;5:516-531.
+
+13. Willmann S, Höhn K, Edginton A, Sevestre M, Solodenko J, Weiss W, Lippert J, Schmitt W. Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn. 2007;34:401-431.

Evaluation/Input/Content/Section1_Introduction.md

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+Risperidone is an atypical antipsychotic used for schizophrenia and other psychiatric indications. It is administered orally and is converted to the active metabolite 9-hydroxyrisperidone, also known as paliperidone. CYP2D6 is an important metabolic pathway for risperidone, while CYP3A4 and transporter processes contribute to parent and metabolite disposition.
+
+This risperidone model is intended to describe plasma concentration-time profiles of risperidone, 9-hydroxyrisperidone, and active moiety across CYP2D6 phenotype and activity-score groups. It supports evaluation of CYP2D6 drug-gene interactions and interacting-drug scenarios where risperidone or 9-hydroxyrisperidone exposure is clinically relevant.
+
+The risperidone parent-metabolite PBPK model was originally developed by [Kneller 2020](References.md). The model was subsequently used in the CYP2D6 activity-score framework by [Rüdesheim 2022](References.md) and in the CYP2D6 drug-drug-gene interaction network by [Rüdesheim 2025](References.md). The clinical data include oral single-dose and multiple-dose administration of risperidone, CYP2D6 phenotype or activity-score stratified groups, and studies with CYP3A or P-gp modulators.
+
+The presented model includes the following features:
+
+- risperidone and 9-hydroxyrisperidone as parent and metabolite compounds,
+- CYP2D6-mediated risperidone metabolism with activity-score dependent k<sub>cat</sub> values,
+- CYP3A4-mediated metabolism and residual sink pathways,
+- P-gp transport for risperidone and 9-hydroxyrisperidone,
+- renal filtration for parent and metabolite,
+- oral tablet administration in the evaluated clinical studies.

Evaluation/Input/Content/Section2.1_Modeling_Strategy.md

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+The general concept of building a PBPK model has previously been described by Kuepfer et al. ([Kuepfer 2016](References.md)). Relevant information on anthropometric and physiological parameters in adults was gathered from the literature and incorporated into PK-Sim as default values for adult simulations ([Willmann 2007](References.md)).
+
+The applied activity and variability of plasma proteins and active processes integrated into PK-Sim are described in the publicly available PK-Sim Ontogeny Database or otherwise referenced for the specific process.
+
+The risperidone model was developed as a parent-metabolite model for risperidone and 9-hydroxyrisperidone. The original model by [Kneller 2020](References.md) described oral risperidone pharmacokinetics by CYP2D6 phenotype. [Rüdesheim 2022](References.md) then used the model in a CYP2D6 activity-score framework, where CYP2D6 metabolic capacity is represented by activity-score dependent k<sub>cat</sub> values.
+
+Clinical studies used for model building covered oral risperidone administration and included data for risperidone and 9-hydroxyrisperidone where available. Model verification used independent oral study arms, including CYP2D6 poor-, normal-, and higher-activity groups and interacting-drug scenarios. Because the active moiety is the sum of parent and metabolite exposure, model performance has to be interpreted separately for risperidone, 9-hydroxyrisperidone, and active moiety.
+
+The model-building workflow first established the parent disposition and the formation of 9-hydroxyrisperidone. CYP2D6-related parameters were then used to describe the shift from parent exposure toward metabolite exposure across phenotype and activity-score groups. Verification focused on whether the final parameter set described independent study arms without additional study-specific adjustment.
+
+The model contains CYP2D6 and CYP3A4 metabolism, P-gp transport, renal filtration, and residual clearance processes. CYP2D6 poor-metabolizer activity is represented by setting CYP2D6 k<sub>cat</sub> to zero, while non-zero activity-score groups use fitted or scaled CYP2D6 k<sub>cat</sub> values.
+
+The evaluated applications are oral risperidone applications with risperidone, 9-hydroxyrisperidone, and active-moiety observations. The major proteins and processes represented explicitly are CYP2D6, CYP3A4, P-gp, plasma protein binding, passive renal filtration, and unspecific hepatic clearance for the metabolite. The parent-metabolite structure is central to the evaluation because a model can describe active moiety while still showing bias in the parent or metabolite alone.
+
+The report therefore presents model diagnostics for the parent and metabolite concentrations and links the clinical-data table to model-building and verification profiles. The intended interpretation is the plausibility of risperidone and 9-hydroxyrisperidone exposure across CYP2D6 status, not a separate reoptimization for each clinical study.
+
+Details about input data are provided in [Section 2.2](#22). Details about the structural model and assumptions are provided in [Section 2.3](#23).

Evaluation/Input/Content/Section2.2_Data.md

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+### 2.2.1 In vitro and physicochemical data
+
+The table below summarizes the drug-dependent inputs documented for the risperidone model. Parameter values are listed for the parent compound and 9-hydroxyrisperidone where they are relevant for interpreting the parent-metabolite simulations.
+
+| Parameter | Unit | Value | Source | Description |
+| --- | ---: | ---: | --- | --- |
+| Risperidone MW | g/mol | 410.48 | [Kneller 2020](References.md) | Parent compound size used in concentration conversions. |
+| Risperidone pK<sub>a</sub> | - | 8.76, 3.11 | [Kneller 2020](References.md) | Basic and acidic ionization constants. |
+| Risperidone f<sub>u</sub> | % | 17.50 | [Kneller 2020](References.md) | Plasma binding input for parent drug. |
+| Risperidone CYP2D6 K<sub>m</sub> to 9-hydroxyrisperidone | µmol/L | 1.10 | [Kneller 2020](References.md) | CYP2D6 affinity parameter for metabolite formation. |
+| Risperidone CYP2D6 k<sub>cat</sub> EM to 9-hydroxyrisperidone | 1/min | 1.07 | Optimized | CYP2D6 metabolic capacity in extensive metabolizers. |
+| Risperidone P-gp K<sub>m</sub> | µmol/L | 26.30 | [Kneller 2020](References.md) | P-gp affinity parameter. |
+| Risperidone P-gp k<sub>cat</sub> | 1/min | 12.72 | Optimized | P-gp transport capacity. |
+| 9-Hydroxyrisperidone f<sub>u</sub> | % | 29.00 | [Kneller 2020](References.md) | Plasma binding input for the active metabolite. |
+| 9-Hydroxyrisperidone P-gp K<sub>m</sub> | µmol/L | 149.60 | [Rüdesheim 2022](References.md) | P-gp affinity parameter for the active metabolite. |
+| 9-Hydroxyrisperidone unspecific CL<sub>hep</sub> | 1/min | 0.08 | Optimized | Residual metabolite elimination. |
+| GFR fraction | - | 1.00 | Assumed | Passive glomerular filtration fraction for parent and metabolite. |
+
+The 9-hydroxyrisperidone P-gp K<sub>m</sub> reported in the publication and supplement by [Rüdesheim 2022](References.md) is erroneous. The model retains the correct value of 149.6 µmol/L.
+
+### 2.2.2 Clinical data
+
+The evaluation uses 19 observed-data records for risperidone and 9-hydroxyrisperidone in peripheral venous blood plasma. The evaluation plan assigns 6 simulations to model building and 6 simulations to model verification.
+
+Model-building clinical data:
+
+| Publication | Arm / Treatment / Information used for model building |
+| --- | --- |
+| [Novalbos 2010](References.md) | Plasma PK profiles in adults after oral, single dose administration of 1 mg risperidone with CYP2D6 AS = 2 status. |
+| [Bondolfi 2002](References.md) | Plasma PK profiles in adults after oral, multiple dose administration of 2 mg risperidone with CYP2D6 poor- and extensive-metabolizer status. |
+| [Markowitz 2002](References.md) | Plasma PK profiles in adults after oral, single dose administration of 1 mg risperidone with CYP2D6 extensive-metabolizer status. |
+| [Darwish 2015](References.md) | Plasma PK profiles in adults after oral, single dose administration of 2 mg risperidone with CYP2D6 extensive-metabolizer status. |
+| [Mahatthanatrakul 2012](References.md) | Plasma PK profiles in adults after oral, single dose administration of 2 mg risperidone with risperidone and 9-hydroxyrisperidone measurements. |
+
+Model-verification clinical data:
+
+| Publication | Arm / Treatment / Information used for model verification |
+| --- | --- |
+| [Novalbos 2010](References.md) | Plasma PK profiles in adults after oral, single dose administration of 1 mg risperidone with CYP2D6 AS = 0, AS = 1, and AS = 3 status. |
+| [Nakagami 2005](References.md) | Plasma PK profiles in adults after oral, single dose administration of 1 mg risperidone with risperidone and 9-hydroxyrisperidone measurements. |
+| [Mahatthanatrakul 2007](References.md) | Plasma PK profiles in adults after oral, single dose administration of 4 mg risperidone. |
+| [Kim 2008](References.md) | Plasma PK profiles in adults after oral risperidone administration with rifampin pretreatment. |