Model and content for Coproporphyrin-I #1
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Same here: @PavelBal, for your review? |
PavelBal
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Jan 13, 2025
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| 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)). |
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| #### 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.
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| The parameter value for `Specific intestinal permeability` was set to 0 to not include intestinal reabsorption. The solubility was obtained from DrugBank (see [Section 2.2.1](#221-in-vitro-and-physicochemical-data)) |
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What is the rationale for this? Why exclude intestinal reabsorption?.
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| ### Distribution <a id="model-parameters-and-assumptions-distribution"></a> | ||
| The synthesis rate was modelled as a zero-order infusion over one year ([Mochizuki 2022](#5-references)). |
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| An important parameter influencing the resulting volume of distribution is lipophilicity. The reported logP value were 2.53 (see [Section 2.2.1](#221-in-vitro-and-physicochemical-data)) which was used in this model. |
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| An important parameter influencing the resulting volume of distribution is lipophilicity. The reported logP value were 2.53 (see [Section 2.2.1](#221-in-vitro-and-physicochemical-data)) which was used in this model. | |
| An important parameter influencing the resulting volume of distribution is lipophilicity. The reported logP value of 2.53 (see [Section 2.2.1](#221-in-vitro-and-physicochemical-data)) is used in this model. |
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| The BCRP expression profiles isbased on high-sensitive real-time RT-PCR ([Nishimura 2003](#5-references)). The reference concentration for OATP1B1 was measured by liquid chromatography tandem mass spectroscopy ([Prasad 2014](#5-references)). Transporter activity was described as saturable process following Michaelis-Menten kinetics, were the `Km` was taken from literature and the `kcat` was optimized based on clinical data (see [Section 2.3.4](#234-automated-parameter-identification)). | ||
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| Additionally, renal clearance was set to 1 according to literature (see [Section 2.2.1](#221-in-vitro-and-physicochemical-data)). |
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What kind of renal clearance? Glomerular filtration with GFR 100% if so - why the assumption?
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| ### Metabolism and Elimination <a id="model-parameters-and-assumptions-metabolism-and-elimination"></a> | ||
| After testing the available organ-plasma partition coefficient and cell permeability calculation methods built in PK-Sim, observed clinical data was best described by choosing the partition coefficient calculation by `Rodgers and Rowland` and cellular permeability calculation by `PK-Sim standard`. |
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Also, the partitionning method used in the model is "PK-Sim" and not R&R.
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| * BCRP |
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Mention that the transporter is called "MRP2" in the model.
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| * BCRP | ||
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| The BCRP expression profiles isbased on high-sensitive real-time RT-PCR ([Nishimura 2003](#5-references)). The reference concentration for OATP1B1 was measured by liquid chromatography tandem mass spectroscopy ([Prasad 2014](#5-references)). Transporter activity was described as saturable process following Michaelis-Menten kinetics, were the `Km` was taken from literature and the `kcat` was optimized based on clinical data (see [Section 2.3.4](#234-automated-parameter-identification)). |
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Reference concentration of OATP in the BCRP section? Copy-paste or leftover?
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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). | |||
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| 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)?
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