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Model and content for Coproporphyrin-I #1

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Initial model and content
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3,550 changes: 3,550 additions & 0 deletions Coproporphyrin-I-Model.json
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2 changes: 1 addition & 1 deletion 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.
Simulated versus observed concentration-time profiles of all data listed in [Section 2.2.2](#222-clinical-data) are presented below.

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1 change: 1 addition & 0 deletions Evaluation/Input/Content/Concentration_time_profiles_verification.md
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2 changes: 1 addition & 1 deletion Evaluation/Input/Content/GOF_diagnostics.md
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Below you find the goodness-of-fit visual diagnostic plots for the PBPK model performance of all data used presented in [Section 2.2.2](#clinical-data).
Below you find the goodness-of-fit visual diagnostic plots for the PBPK model performance of all data used presented in [Section 2.2.2](#222-clinical-data).

The first plot shows observed versus simulated plasma concentration, the second weighted residuals versus time.

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I think the residuals over time plot makes no sense here.

It might also be worth mentioning that the model represents one mean state with constant endogenous concentrations, and this explains the horizontal spread of the residuals in the first plot. Also, what is the assumed basal concentration and why (source)?

33 changes: 29 additions & 4 deletions Evaluation/Input/Content/References.md
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**Kuepfer 2016** 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 Oct;5(10):516-531. doi: 10.1002/psp4.12134. Epub 2016 Oct 19.

**PK-Sim Ontogeny Database Version 7.3** ([https://github.com/Open-Systems-Pharmacology/OSPSuite.Documentation/blob/38cf71b384cfc25cfa0ce4d2f3addfd32757e13b/PK-Sim%20Ontogeny%20Database%20Version%207.3.pdf](https://github.com/Open-Systems-Pharmacology/OSPSuite.Documentation/blob/38cf71b384cfc25cfa0ce4d2f3addfd32757e13b/PK-Sim%20Ontogeny%20Database%20Version%207.3.pdf))
**Bednarczy 2016** Bednarczyk D, Boiselle C. Organic anion transporting polypeptide (OATP)-mediated transport of coproporphyrins I and III. Xenobiotica. 2016 May 3;46(5):457-66.

**Drugbank** Knox C, Wilson M, Klinger CM, et al. DrugBank 6.0: the DrugBank Knowledgebase for 2024. Nucleic Acids Res. 2024 Jan 5;52(D1):D1265-D1275. doi: 10.1093/nar/gkad976

**Gilibili 2017** Gilibili RR, Chatterjee S, Bagul P, Mosure KW, Murali BV, Mariappan TT, Mandlekar S, Lai Y. Coproporphyrin-I: a fluorescent, endogenous optimal probe substrate for ABCC2 (MRP2) suitable for vesicle-based MRP2 inhibition assay. Drug Metabolism and Disposition. 2017 Jun 1;45(6):604-11.

**Kimoto 2022** E Kimoto, C Costales, MA West, YA Bi, M Vourvahis, A David Rodrigues, MVS Varma (2022). Biomarker-Informed Model-Based Risk Assessment of Organic Anion Transporting Polypeptide 1B Mediated Drug-Drug Interactions. *Clin Pharmacol Ther*, Feb;111(2):404-415.

**Lai 2016** Lai Y, Mandlekar S, Shen H, Holenarsipur VK, Langish R, Rajanna P, Murugesan S, Gaud N, Selvam S, Date O, Cheng Y. Coproporphyrins in plasma and urine can be appropriate clinical biomarkers to recapitulate drug-drug interactions mediated by organic anion transporting polypeptide inhibition. Journal of Pharmacology and Experimental Therapeutics. 2016 Sep 1;358(3):397-404.

**Lou 2015** Z Luo, Y Zhang, J Gu, P Feng, Y Wang (2015). Pharmacokinetic Properties of Single- and Multiple-Dose Pitavastatin Calcium Tablets in Healthy Chinese Volunteers. *Curr Ther Res Clin Exp*, Mar 3;77:52-7.

**Meyer 2012** Meyer M, Schneckener S, Ludewig B, Kuepfer L, Lippert J. (2012). Using expression data for quantification of active processes in physiologically based pharmacokinetic modeling. *Drug Metab Dispos*. May;40(5), 892-901.

**Mochizuki 2022** T Mochizuki, Y Aoki, T Yoshikado, K Yoshida, Y Lai, H Hirabayashi, Y Yamaura, K Rockich, K Taskar, T Takashima, X Chu, MJ Zamek-Gliszczynski, J Mao, K Maeda, K Furihata, Y Sugiyama, H Kusuhara (2022). Physiologically-based pharmacokinetic model-based translation of OATP1B-mediated drug-drug interactions from coproporphyrin I to probe drugs. *Clin Transl Sci.* Jun;15(6):1519-1531.

**Mori 2020** D Mori, E Kimoto, B Rago, Y Kondo, A King‐Ahmad, R Ramanathan, LS Wood, JG Johnson, VH Le, M Vourvahis, A David Rodrigues (2020). Dose‐dependent inhibition of OATP1B by rifampicin in healthy volunteers: comprehensive evaluation of candidate biomarkers and OATP1B probe drugs. *Clinical Pharmacology & Therapeutics*, Apr;107(4):1004-13.

**Nishimura 2003** Nishimura M, Yaguti H, Yoshitsugu H, Naito S, Satoh T. (2003). Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. *Yakugaku Zasshi.* May;123(5), 369-75.

**Prasad 2013** Prasad B, Lai Y, Lin Y, Unadkat JD (2013) Interindividual variability in the hepatic expression of the human breast cancer resistance protein (BCRP/ABCG2): effect of age, sex, and genotype. Journal of pharmaceutical sciences 102(3):787–93

**Prasad 2014** Prasad B, Evers R, Gupta A, Hop CECA, Salphati L, Shukla S, Ambudkar SV, Unadkat JD (2014) Interindividual variability in hepatic organic anion-transporting polypeptides and PGlycoprotein (ABCB1) protein expression: Quantification by liquid chromatography tandem mass spectroscopy and influence of genotype, age, and sex. Drug Metabolism and Disposition 42(1):78–88

**Takehara 2018** I Takehara, T Yoshikado, K Ishigame, D Mori, KI Furihata, N Watanabe, O Ando, K Maeda, Y Sugiyama, H Kusuhara (2018). Comparative study of the dose-dependence of OATP1B inhibition by rifampicin using probe drugs and endogenous substrates in healthy volunteers. *Pharmaceutical research*, Jul;35:1-3.

**Yoshikado 2018** Yoshikado T, Toshimoto K, Maeda K, Kusuhara H, Kimoto E, Rodrigues AD, Chiba K, Sugiyama Y. PBPK modeling of coproporphyrin I as an endogenous biomarker for drug interactions involving inhibition of hepatic OATP1B1 and OATP1B3. CPT: pharmacometrics & systems pharmacology. 2018 Nov;7(11):739-47.

**Zhang 2020** Zhang Y, Holenarsipur VK, Kandoussi H, Zeng J, Mariappan TT, Sinz M, Shen H. Detection of Weak Organic Anion–Transporting Polypeptide 1B Inhibition by Probenecid with Plasma-Based Coproporphyrin in Humans. Drug Metabolism and Disposition. 2020 Oct 1;48(10):841-8.

**Schlender 2016** Schlender JF, Meyer M, Thelen K, Krauss M, Willmann S, Eissing T, Jaehde U. Development of a Whole-Body Physiologically Based Pharmacokinetic Approach to Assess the Pharmacokinetics of Drugs in Elderly Individuals. Clin Pharmacokinet. 2016 Dec;55(12):1573-1589.

**Dummy YEAR** Dummy D, Doe J, Doe A. Pharmacokinetic study of COMPOUND. JOURNAL. YEAR Mon;ISSUE:PAGES. doi: DOI.
14 changes: 10 additions & 4 deletions Evaluation/Input/Content/Section1_Introduction.md
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COMPOUND is an active, highly selective ... (Information about Pharmacology)
Coproporphyrin-I is an endogenous biomarker for OATP1B1 transport, as this is the main route of excretion of Coproporphyrin-I in combination with elimination via BCRP to the bile. In addition, a smaller fraction of Coproporphyrin-I is excreted through urine.

COMPOUND is ... (Information about relevant Pharmacokinetics)
This Coproporphyrin-I model is intended to be used as an endogenous marker to estimate the inhibiton constants for OATP1B1 perpetrators.

The herein presented model building and evaluation report evaluates the performance of the PBPK model for COMPOUND in (healthy) adults.
This whole-body PBPK model of Coproporphyrin-I has been developed using published pharmacokinetic clinical data by Mori 2020 ([Mori 2020](#5-references)), Takehara 2018 ([Takehara 2018](#5-references)), Lai 2016 ([Lai 2016](#5-references)) and Zhang 2020 ([Zhang 2020](#5-references)).
The model has then been evaluated by simulating clinical studies and comparing with respective observed data.
The clinical data included both baseline and drug-drug interaction (DDI) studies.

The presented COMPOUND PBPK model as well as the respective evaluation plan and evaluation report are provided open-source ([https://github.com/Open-Systems-Pharmacology/COMPOUND-Model](https://github.com/Open-Systems-Pharmacology/COMPOUND-Model)).
The presented model includes the following features:

- transport by OATP1B1/B3,
- transport by BCRP
- renal clearance by glomerular filtration,
- intracellular liver synthesis modeled as a zero-order infusion.
15 changes: 6 additions & 9 deletions 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](#main-references)) Regarding the relevant anthropometric (height, weight) and physiological parameters (e.g. blood flows, organ volumes, binding protein concentrations, hematocrit, cardiac output) in adults was gathered from the literature and has been previously published ([PK-Sim Ontogeny Database Version 7.3](#main-references)). The information was incorporated into PK-Sim® and was used as default values for the simulations in adults.
The general concept of building a PBPK model has previously been described by Kuepfer et al. ([Kuepfer 2016](#5-references)). Relevant information on anthropometric (height, weight) and physiological parameters (e.g. blood flows, organ volumes, binding protein concentrations, hematocrit, cardiac output) in adults was gathered from the literature and has been previously published ([Willmann 2007](#5-references)). The information was incorporated into PK-Sim® and was used as default values for the simulations in adults.

The applied activity and variability of plasma proteins and active processes that are integrated into PK-Sim® are described in the publicly available PK-Sim® Ontogeny Database Version 7.3 ([Schlender 2016](#main-references)) or otherwise referenced for the specific process.
The applied activity and variability of plasma proteins and active processes that are integrated into PK-Sim® are described in the publicly available PK-Sim® Ontogeny Database Version 7.3 ([PK-Sim Ontogeny Database Version 7.3](#5-references)) or otherwise referenced for the specific process.

First, a base mean model was built using clinical Phase I data including selected single dose studies with intravenous and oral applications (capsule) of dapagliflozin to find an appropriate structure to describe the pharmacokinetics in plasma. The mean PBPK model was developed using a typical European individual. The relative tissue specific expressions of enzymes predominantly being involved in the metabolism of COMPOUND...
A mean model was built based on clinical data from studies of baseline Coproporphyrin-I and after administation of OATP1B perpetrators by Mori 2020 ([Mori 2020](#5-references)), Takehara 2018 ([Takehara 2018](#5-references)),, Lai 2016 ([Lai 2016](#5-references)) and Zhang 2020 ([Zhang 2020](#5-references)). The studies reported mean plasma concentrations of Coproporphyrin-I. The mean PBPK model was developed using a mean individual based on the demographic data for each study and if no demographic data were provided the following values were used; male, European, 30 years of age, 73 kg body weight and 176 cm body height. The relative tissue-specific expressions of the enzyme and transporter predominantly being involved in the metabolism/transport of Coproporphyrin-I (OATP1B1 and BCRP) were considered ([Meyer 2012](#5-references)). A zero-order infusion of 1.09 mg/kg over one year were applied to model the synthesis rate of Coproporphyrin-I ([Mochizuki 2022](#5-references)).

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A mean model was built based on clinical data from studies of baseline Coproporphyrin-I and after administation of OATP1B perpetrators by Mori 2020 ([Mori 2020](#5-references)), Takehara 2018 ([Takehara 2018](#5-references)),, Lai 2016 ([Lai 2016](#5-references)) and Zhang 2020 ([Zhang 2020](#5-references)). The studies reported mean plasma concentrations of Coproporphyrin-I. The mean PBPK model was developed using a mean individual based on the demographic data for each study and if no demographic data were provided the following values were used; male, European, 30 years of age, 73 kg body weight and 176 cm body height. The relative tissue-specific expressions of the enzyme and transporter predominantly being involved in the metabolism/transport of Coproporphyrin-I (OATP1B1 and BCRP) were considered ([Meyer 2012](#5-references)). A zero-order infusion of 1.09 mg/kg over one year were applied to model the synthesis rate of Coproporphyrin-I ([Mochizuki 2022](#5-references)).
A mean model was built based on clinical data from studies of baseline Coproporphyrin-I and after administation of OATP1B perpetrators by Mori 2020 ([Mori 2020](#5-references)), Takehara 2018 ([Takehara 2018](#5-references)), Lai 2016 ([Lai 2016](#5-references)) and Zhang 2020 ([Zhang 2020](#5-references)). The studies reported mean plasma concentrations of Coproporphyrin-I. The mean PBPK model was developed using a mean individual based on the demographic data for each study. If no demographic data were provided, the following values were used: male, European, 30 years of age, 73 kg body weight and 176 cm body height. The relative tissue-specific expressions of the enzyme and transporter predominantly being involved in the metabolism/transport of Coproporphyrin-I (OATP1B1 and BCRP) were considered ([Meyer 2012](#5-references)). A zero-order infusion of 1.09 mg/kg over one year were applied to model the synthesis rate of Coproporphyrin-I ([Mochizuki 2022](#5-references)).

Unknown parameters (see below) were identified using the Parameter Identification module provided in PK-Sim®. Structural model selection was mainly guided by visual inspection of the resulting description of data and biological plausibility.
A specific set of parameters (see below) was optimized to describe the disposition of Coproporphyrin-I using the Parameter Identification module provided in PK-Sim®. Structural model selection was mainly guided by visual inspection and total error of the resulting description of data, 95% confidence interval of the identified parameter values and biological plausibility.

Once the appropriate structural model was identified, additional parameters for tablet formulations were identified.
Details about input data (physicochemical, *in vitro* and clinical) can be found in [Section 2.2](#22-data-used).

The model was then verified by simulating:
Details about the structural model and its parameters can be found in [Section 2.3](#23-model-parameters-and-assumptions).

- ...

Details about input data (physicochemical, *in vitro* and clinical) can be found in [Section 2.2](#methods-data).

Details about the structural model and its parameters can be found in [Section 2.3](#model-parameters-and-assumptions).

56 changes: 27 additions & 29 deletions Evaluation/Input/Content/Section2.2_Data.md
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### In vitro / physico-chemical Data <a id="invitro-and-physico-chemical-data"></a>
### 2.2.1 In vitro and physicochemical data

A literature search was performed to collect available information on physicochemical properties of dapagliflozin. The obtained information from literature is summarized in the table below.
A literature search was performed to collect available information on physicochemical properties of Coproporphyrin-I. The obtained information from literature is summarized in the table below, and is used for model building.

| **Parameter** | **Unit** | **Value** | Source | **Description** |
| :-------------- | -------- | --------- | ------------------------------------------ | ----------------------------------------------- |
| MW | g/mol | | [Dummy YEAR](#main-references) | Molecular weight |
| pK<sub>a</sub> | | | [DrugBank DB06292](#main-references) | Acid dissociation constant |
| Solubility (pH) | | | [Dummy YEAR](#main-references) | Aqueous Solubility, FaSSIF, ... |
| logP | | | [Dummy YEAR](#main-references) (experimental) | Partition coefficient between octanol and water |
| fu | % | | [Dummy YEAR](#main-references) | Fraction unbound in plasma |
| B/P ratio | | | [Dummy YEAR](#main-references) | Blood to plasma ratio |
| ... | | | | .... |
| **Parameter** | **Unit** | **Value** | Source | **Description** |
| :---------------------- | -------- | --------- | ------------------------------------ | ------------------------------------------------------------ |
| MW | g/mol | 654.71 | [Yoshikado 2018](#5-references) | Molecular weight |
| pK<sub>a</sub> (acid) | | 3.56 | [Yoshikado 2018](#5-references) | acid dissociation constant of conjugate acid |
| pK<sub>a</sub> (base) | | 5.18 | [Yoshikado 2018](#5-references) | acid dissociation constant of conjugate base |
| Solubility (pH7.4) | mg/mL | 0.03 | [DrugBank](#5-references) | Aqueous Solubility in pH 7.4 |
| logP | | 2.53 | [Yoshikado 2018](#5-references) | Partition coefficient between octanol and water |
| fu | % | 0.66 | [Yoshikado 2018](#5-references) | Fraction unbound in plasma |
| K<sub>m</sub> OATP1B1 | µmol/L | 0.13 | [Bednarczy 2016](#5-references) | OATP1B1 Michaelis-Menten constant |
| K<sub>m</sub> BCRP | µmol/L | 7.7 | [Gilibili 2017](#5-references)| BCRP Michaelis-Menten |
| Synthesis rate | nmol/h/kg | 0.19 | [Mochizuki 2022](#5-references) | Endogenous synthesis rate |
| Renal clearance | L/h/kg | 0.04 | [Mochizuki 2022](#5-references) | elimination rate via kidneys |

### Clinical Data <a id="clinical-data"></a>
### 2.2.2 Clinical data

A literature search was performed to collect available clinical data on dapagliflozin in healthy adults.
A literature search was performed to collect available clinical data on Coproporphyrin-I in adults.

#### Model Building <a id="model-building"></a>
The following publications were found in adults for model building:

The following studies were used for model building (training data):
| Publication | Arm / Treatment / Information used for model building |
| :---------------------------- | :----------------------------------------------------------- |
| [Mori 2020](#5-references) | Baseline PK profiles in healthy subjects of Coproporphyrin-I|
| [Takehara 2018](#5-references) | Baseline and DDI plasma PK profiles in healthy subjects of Coproporphyrin-I|
| [Lai 2016](#5-references) | Baseline and DDI plasma PK profiles in healthy subjects of Coproporphyrin-I|
| [Zhang 2020](#5-references) | Baseline and DDI plasma PK profiles in healthy subjects of Coproporphyrin-I|

| Publication | Arm / Treatment / Information used for model building |
| :-------------------------- | :---------------------------------------------------- |
| [Dummy YEAR](#main-references) | Healthy Subjects with a single dose of X mg |
| ... | ... |
| ... | ... |
| ... | ... |

#### Model Verification <a id="model-verification"></a>
The following dosing scenarios were simulated and compared to respective data for model verification, see the OATP1B1/3-DDI qualification report for model performance:

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If the DDI report is not available yet, remove the statement and add it when the report will become available.

The following studies were used for model verification:
| Scenario | Data reference |
| ------------------------------------------------------------ | ------------------------------------ |
| DDI with 150 mg, 300 mg and 600 mg rifampicin |[Mori 2020](#5-references) |

| Publication | Arm / Treatment / Information used for model building |
| :-------------------------- | :---------------------------------------------------- |
| [Dummy YEAR](#main-references) | Healthy Subjects with a single dose of Y mg |
| ... | ... |
| ... | ... |
| ... | ... |

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