Partition Coefficient
Antibody partition coefficients are defined on a per-compartment basis, \(P_{dist,compartment}\), for disease, tox, and peripheral compartments. \(P_{dist}\), along with \(T_{dist}\), controls the transport rate of drug between the Central Compartment and the Compartment of interest (Peripheral, Disease, Tox). \(P_{dist}\) is defined as the ratio of drug concentration in the compartment of interest relative to central compartment at equilibrium, in the absence of other synthesis or clearance mechanisms.
For ADCs, \(P_{dist,PL}\) refers to the ratio of the unbound intracellular payload concentration relative to the extracellular concentration.
Partition Coefficients in Assess
For 4-compartment models, \(P_{dist}\) should be defined for all compartments that are being simulated. To turn off a compartment, set \(P_{dist} = 0\) for the compartment. This value eliminates drug transport into the compartment. Other parameters such as ligand or receptor concentration may also need to be set to 0 to fully eliminate the compartment, depending on the model.
All recommendations for \(P_{dist}\) are based on the use of physiological compartment volumes in the model. Recommendations change if non-physiological compartment volumes are used.
Peripheral Compartment
For antibody-based biotherapeutics, transport between the central and peripheral compartment defines the distribution phase of drug PK. Since antibodies and antibody-based biotherapeutics generally display consistent pharmacokinetic behavior, \(P_{dist,peripheral}\) can be set to typical values in the absence of data. When PK data is available, \(P_ {dist,peripheral}\) can be fit to data.
When empirical 2-compartment PK model parameters are available, \(P_{dist,peripheral}\) can be defined as \(\frac{V2}{V_ {peripheral}}\) where \(V2\) is the empirical volume of the second compartment in the PK model.
Disease and Tox Compartments
Transport parameters to the disease and tox compartments depend on the tissues being described by these compartments. Drug distribution into tissues is challenging to measure, and data is often sparse. In all cases, scanning a range to determine the importance of \(P_{dist,disease}\) and \(P_{dist,tox}\) on simulation results is recommended.
While the extent of drug penetration into a tissue can be influenced by several factors including drug size (Thurber, Schmidt, and Wittrup 2008; Krol et al. 1999), disease and tox compartments are treated as well-mixed compartments with uniform drug concentration. Therefore, limited drug penetration is represented by lower average drug concentration within the compartment.
Experimental Data
There are two main sources of information that inform \(P_{dist}\) for antibodies: physiologically-based pharmacokinetic (PBPK) models of antibody disposition (Shah and Betts 2012, Shah and Betts 2013, Cao and Jusko 2014) and direct measurements, primarily in preclinical animal models (Davidsson et al. 2015, Jadhav et al. 2017, Kratochwil et al. 2018, Dragatin et al. 2015).
Experimental methods include quantitation of radiolabeled antibodies in blood and various tissue after systemic administration, ELISA-based quantification of perfused vs. non-perfused tissues after systemic administration, and quantification from direct sampling of interstitial space through microdialysis. When interpreting experimental data, it can be important to note whether target binding is affecting the antibody distribution (using non-binding antibodies give the best information on antibody transport), and whether drug in the blood vessels is contributing to tissue drug concentrations. Other considerations include whether disease state alters drug transport.
Typical Values
Peripheral Compartment
\(P_{dist,peripheral}\) for typical antibodies in cyno and human, based on literature reported antibody PK, are listed below.
| Species | \(P_{dist,peripheral}\) | Reference |
|---|---|---|
| Human | 0.21 | Betts et al. 2018, Singh et al. 2015, Deng et al. 2011 |
| Cyno | 0.19 | Dirks and Meibohm 2010, Betts et al. 2018, Davda et al. 2014, Singh et al. 2015 |
Disease and Tox Compartments
Antibody biodistribution coefficient of tissues were calculated for human, mouse, rat, monkey, in Shah and Betts, 2013.
The model-generated data suggest that there is a linear relationship between plasma and tissue mAb concentration for all tissues. The relationship was similar for all four of the species analyzed and also seemed constant over a wide range of concentrations.
Across typical preclinical species and humans, \(P_{dist}\) for disease and tox compartments can be set based on tissue:
| Tissue | Antibody Biodistribution Coefficient (\(P_{dist}\)) |
|---|---|
| Lung | 0.149 |
| Heart | 0.102 |
| Kidney | 0.137 |
| Muscle | 0.0397 |
| Skin | 0.157 |
| Small Int. | 0.0522 |
| Large Int. | 0.0503 |
| Spleen | 0.128 |
| Liver | 0.121 |
| Bone | 0.0727 |
| Stomach | 0.0498 |
| Lymph nodes | 0.0846 |
| Fat | 0.0478 |
| Brain | 0.00351 |
| Pancreas | 0.0640 |
| Testes | 0.0588 |
| Thyroid | 0.675 |
| Thymus | 0.0552 |
\(P_{dist}\) can be measured using alternative approaches. As part of sensitivity analysis, the following ranges cover a broad selection of PBPK models and pre-clinical animal models.
| Antibody Distribution Coefficient (\(P_{dist}\)) | Notes | Reference |
|---|---|---|
| 0.05 - 0.15 | Estimated antibody biodistribution into human tissues (and preclinical animal model species) | Shah and Betts, 2013 |
| 0.07 - 0.38 | Estimated range for "tight" or "leaky" tissues using mPBPK model analyses of 72 mAbs (in human) | Cao and Jusko, 2014 |
| 0.01 - .04 | Measured from perfused tissues in mouse | Davidsson et al. 2015 |
| 0.02 - 0.06 | Measured from interstitial fluid by microdialysis in mouse | Jadhav et al. 2017 |
| 0.01 - 0.28 | Measured from perfused tissues by CRDS in mouse | Kratochwil et al. 2018 |
| 0.23 (healthy) 0.28-0.39 (psoriasis) |
Measured Secukinumab (anti-IL-17) levels in skin ISF by microperfusion in human patients. Baseline IL-17 levels in psoriasis patients low compared to drug concentrations. | Dragatin et al. 2015 |
Special notes when disease compartment is a tumor
When tumor is the disease compartment, the recommended value for \(P_{dist,disease}\) is 0.30 in the absence of other data. This recommendation is supported by the data below.
| Antibody Distribution Coefficient (\(P_{dist}\)) | Notes | Reference |
|---|---|---|
| 0.24 - 0.34 | PBPK model and measurements of antibody distribution to HT-29 and LS174T xenograft tumors treated with non-targeting or anti-CEA antibody | Abuqayyas and Balthasar 2012 |
| 0.30 | Tumor interstitial to plasma radioactivity ratio for PD-L1 antibody | Deng et al. 2016 |
| 0.38 - 0.75 | Rough calculation of interstitial to plasma concentrations for non-targeting antibody in 2 different xenograft models. Transport rates for 3-compartment PK model are given. | Shockley et al. Cancer Research, 1992 |
References
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