BAY794620-Model.RmdBuilding and evaluation of a PBPK model for BAY 79-4620 in mice
| Version | 1.0-OSP11.0 |
|---|---|
| based on Model Snapshot and Evaluation Plan | https://github.com/Open-Systems-Pharmacology/BAY794620-Model/releases/tag/v1.0 |
| OSP Version | 11.0 |
| Qualification Framework Version | 3.0 |
This evaluation report and the corresponding PK-Sim project file are filed at:
https://github.com/Open-Systems-Pharmacology/OSP-PBPK-Model-Library/
1 Introduction
BAY 79-4620 is an antibody–drug conjugate consisting of a human IgG1 mAb directed against human carbonic anhydrase IX (CA IX) conjugated to the toxophore monomethylauristatin E (MMAE) via a valine-citrulline based linker (Petrul 2012).
For BAY 79-4620, tissue concentration-time profiles for a large number of different mice tissues were measured and used together with pharmacokinetic (PK) data from 5 other compounds to identify unknown parameters during the development of the generic large molecule physiologically based pharmacokinetic (PBPK) model in PK-Sim (Niederalt 2018).
The herein presented evaluation report evaluates the performance of a PBPK model for BAY 79-4620 in xenograft mice for the PK data used for the development of the generic large molecule model in PK-Sim. A standard PK-Sim model was used without an additional tumor organ and without target mediated drug disposition effects from CA IX binding in the tumor - in contrast to the model which has been used in Ref. (Niederalt 2018).
The presented BAY 79-4620 PBPK model as well as the respective evaluation plan and evaluation report are provided open-source (https://github.com/Open-Systems-Pharmacology/BAY794620-Model).
2 Methods
2.1 Modeling Strategy
The development of the large molecule PBPK model in PK-Sim® has previously been described by Niederalt et al. (Niederalt 2018). In short, the model was built as an extension of the PK-Sim® model for small molecules incorporating (i) the two-pore formalism for drug extravasation from blood plasma to interstitial space, (ii) lymph flow, (iii) endosomal clearance and (iv) protection from endosomal clearance by neonatal Fc receptor (FcRn) mediated recycling.
For model development and evaluation, PK data were used from compounds with a wide range of solute radii and from different species. The PK data used for parameter estimation were from the following compounds: antibody–drug conjugate BAY 79-4620 in mice (Bayer in house data), antibody 7E3 in wild-type and FcRn knockout mice (Garg 2007, Garg2009), domain antibody dAb2 in mice (Sepp 2015), antibodies MEDI-524 and MEDI-524-YTE in monkeys (Dall’Acqua 2006), and antibody CDA1 in humans (Taylor 2008). The PK data used for model evaluation were from inulin in rats (Tsuji1983) and tefibazumab in humans (Reilly 2005).
The PBPK model including the estimated physiological parameters as described by Niederalt et al. (Niederalt 2018) is available in the Open Systems Pharmacology Suite from version 7.1 onwards.
This evaluation report focuses on the PBPK model for the antibody–drug conjugate BAY 79-4620.
Details about input data (physicochemical, in vitro and PK) can be found in Section 2.2.
Details about the structural model and its parameters can be found in Section 2.3.
2.2 Data
2.2.1 In vitro / physico-chemical Data
A literature search was performed to collect available information on physicochemical properties of BAY 79-4620. The obtained information from literature is summarized in the table below.
| Parameter | Unit | Value | Source | Description |
|---|---|---|---|---|
| MW | g/mol | 152000 | Bayer in-house data | Molecular weight |
| r | nm | 5.34 | Taylor 1984 | Hydrodynamic solute radius |
| Kd (FcRn) | µM | 0.082 | Zhou 2003 | Dissociation constant for binding of a humane IgG1 antibody to murine FcRn at pH 6 |
2.2.2 PK Data
The biodistribution data from mice for BAY 79-4620 were Bayer AG in house data taken from two studies:
| Data | Description |
|---|---|
| Whole-body autoradiography | Female nude mice (NMRI nu/nu), bearing HT-29 human colon carcinoma xenografts, were dosed intravenously with 1.25 mg/kg body weight of 125I-labeled BAY 79-4620. The distribution of total radioactivity in organs and tissues was determined by quantitative whole-body autoradiography after sacrificing the mice (two per time) at various time points after administration. |
| Wet-tissue dissection study | Female nude mice (NMRI nu/nu), bearing HT-29 human colon carcinoma xenografts, were dosed intravenously with 2 µCi (approx. 500 ng) of 125I-labeled BAY 79-4620. The distribution of total radioactivity in organs and tissues was determined after sacrificing the mice (three per time) and dissection of the organs at various time points after administration by determination of radioactivity using a gamma-counter. The concentrations were reported as percentage of dose / g tissue. These values were converted to concentrations in ng/ml assuming a density of 1 g/ml for all tissues except for bone for which a density of 1.5 g/ml was assumed (as in Ref. Baxter 1994). |
2.3 Model Parameters and Assumptions
2.3.2 Distribution
The standard lymph and fluid recirculation flow rates and the standard vascular properties of the different tissues (hydraulic conductivity, pore radii, fraction of flow via large pores) from PK-Sim were used. BAY 79-4620, among other compounds, has been used to identify these lymph and fluid recirculation flow rates used in PK-Sim (Niederalt 2018).
A standard PK-Sim model was used without an additional tumor organ - in contrast to the model which has been used in Ref. (Niederalt 2018). It was assumed that BAY 79-4620 is not cross-reactive to murine CA IX, i.e. there is no drug-target binding due to the neglect of tumor tissue in the present PK-Sim standard model (again in contrast to the model used in Ref. (Niederalt 2018)).
2.3.3 Metabolism and Elimination
The FcRn mediated clearance present in the standard PK-Sim model was used as only clearance process (in contrast to the model used in Ref. (Niederalt 2018), where there is an additional target mediated clearance process in tumor tissue). The affinity to FcRn in the endosomal space was fitted to the PK data. The same value as fitted in Ref. (Niederalt 2018) was used since the contribution from target mediated clearance was small.
2.3.4 Tissue Concentrations
For the comparison with experimental data the parameters Fraction of blood for sampling used in the Observer for the tissue concentrations were set for all organs to 0.18 for comparison with tissue dissection data and to 0.42 for comparison with autoradiography data according to the fit results (across compounds) in Ref. (Niederalt 2018). (The parameter Fraction of blood for sampling specifies residual blood in tissue as ratio of blood volume contributing to the measured tissue concentration to the total in vivo capillary blood volume.)
In the present evaluation report, the experimental intestine concentrations from the tissue dissection study were compared to simulated organ concentrations for small and large intestine separately in the goodness of fit plots as well as in the concentration-time profile plot.
2.3.5 Automated Parameter Identification
The table shows the parameter values that were specified in the model based on the parameter identification reported in Ref. (Niederalt 2018), and which were not included in the PK-Sim database since version 7.1.
| Model Parameter | Optimized Value | Unit |
|---|---|---|
Kd(FcRn) in endosomal space |
12.7 | µmol/L |
Fraction of blood for sampling (all organs) - for comparison with tissue dissection data |
0.18 | |
Fraction of blood for sampling (all organs) - for comparison with autoradiography data |
0.42 |
3 Results and Discussion
The PBPK model for BAY 79-4620 was evaluated with blood and tissue PK data from mice.
These PK data have been used together with PK data from 5 other compounds to simultaneously identify parameters during the development of the generic model for proteins and large molecules in PK-Sim (Niederalt 2018).
The fitted dissociation constant for binding to FcRn in the endosomal space is rather high compared to usual dissociation constants. This might reflect a lowered affinity to FcRn due to the conjugation of the toxophore or alternatively is a surrogate for a clearance process not represented in the model.
The next sections show:
- the final model parameters for the building blocks: Section 3.1.
- the overall goodness of fit: Section 3.2.
- simulated vs. observed concentration-time profiles for the clinical studies used for model building and for model verification: Section 3.3.
3.1 Final input parameters
The compound parameter values of the final PBPK model are illustrated below.
Compound: BAY794620
Parameters
| Name | Value | Value Origin | Alternative | Default |
|---|---|---|---|---|
| Solubility at reference pH | 99999 mg/l | Other-/Dummy value not used in the simulation | Measurement | True |
| Reference pH | 7 | Other-/Dummy value not used in the simulation | Measurement | True |
| Lipophilicity | -5 Log Units | Other-/Dummy value not used in the simulation | Measurement | True |
| Fraction unbound (plasma, reference value) | 1 | Other-Assumption | Measurement | True |
| Is small molecule | No | |||
| Molecular weight | 152000 g/mol | |||
| Plasma protein binding partner | Unknown | |||
| Radius (solute) | 0.00534 µm | Publication-Taylor1984 | ||
| Kd (FcRn) in endosomal space | 12.7 µmol/l | Parameter Identification |
3.2 Diagnostics Plots
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.
The first plot shows observed versus simulated plasma concentration, the second weighted residuals versus time.
Table 3-1: GMFE for Goodness of fit plot for concentration in blood and tissues
| Group | GMFE |
|---|---|
| BAY 79-4620 - autoradiography | 1.48 |
| BAY 79-4620 - tissue dissection | 1.62 |
| All | 1.53 |
Figure 3-1: Goodness of fit plot for concentration in blood and tissues
Figure 3-2: Goodness of fit plot for concentration in blood and tissues
3.3 Concentration-Time Profiles
Simulated versus observed concentration-time profiles of all data listed in Section 2.2.2 are presented below.
Figure 3-3: Blood - lin scale
Figure 3-4: Blood - log scale
Figure 3-5: Lung
Figure 3-6: Kidney
Figure 3-7: Skin
Figure 3-8: Muscle
Figure 3-9: Spleen
Figure 3-10: Liver
Figure 3-11: Heart
Figure 3-12: Fat
Figure 3-13: Brain
Figure 3-14: Stomach
Figure 3-15: Pancreas
Figure 3-16: Small Intestine
Figure 3-17: Ovaries
Figure 3-18: Blood - lin scale
Figure 3-19: Blood - log scale
Figure 3-20: Lung
Figure 3-21: Kidney
Figure 3-22: Bone
Figure 3-23: Muscle
Figure 3-24: Spleen
Figure 3-25: Liver
Figure 3-26: Heart
Figure 3-27: Fat
Figure 3-28: Brain
Figure 3-29: Stomach
Figure 3-30: Pancreas
Figure 3-31: Intestine
Figure 3-32: Ovaries
4 Conclusion
The herein presented PBPK model overall adequately describes the pharmacokinetics of BAY 79-4620 in mice. The tissue concentrations from the low dose tissue dissection study (dose approximately 0.025 mg/kg) are similarly well described as the tissue concentrations from the autoradiography study (dose 1.25 mg/kg), with the exception of the late concentrations at 168 h after administration from the tissue dissection study which are underestimated by the model. The largest deviations between measured and simulated concentration-time profiles are observed for spleen concentrations which are overestimated by the model and brain concentrations which are underestimated.
The PK data had been used during the development of the generic large molecule PBPK model in PK-Sim (Niederalt 2018) together with PK data from 5 other compounds (7E3, CDA1, dAb2, MEDI-524 & MEDI-524-YTE).
5 References
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