Abstract
The prediction of bioavailability is one of the major barriers in the clinical translation of subcutaneously (SC) administered therapeutic monoclonal antibodies (mAbs) due to the lack of reliable in vitro and preclinical in vivo predictive models. Recently, multiple linear regression (MLR) models were developed to predict human SC bioavailability of mAbs using human linear clearance (CL) and isoelectric point (pI) of the whole antibody or Fv regions as independent variables. Unfortunately, these models cannot be applied to mAbs at the preclinical development stage because human CLs of these mAbs are unknown. In this study, we predicted human SC bioavailability of mAbs using preclinical data only by two approaches. In the first approach, allometric scaling was used to predict human linear CL from non-human primate (NHP) linear CL. The predicted human CL and the pI of the whole antibody or Fv regions were then incorporated into two previously published MLR models to predict the human bioavailability of 61 mAbs. In the second approach, two MLR models were developed using NHP linear CL and the pI of whole antibody or Fv regions of 41 mAbs in a training set. The two models were validated using an independent test dataset containing 20 mAbs. The four MLR models generated 77–85% of predictions within 0.8- to 1.2-fold deviations from observed human bioavailability. Overall, this study demonstrated that human SC bioavailability of mAbs at the preclinical stage could be predicted using NHP CL and pI of mAbs.
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The author confirms that the data supporting findings of this study are available within the article and supplementary materials.
Abbreviations
- 3D_pI:
-
3D isoelectric point
- AUC0–tau :
-
Area under the plasma concentration–time curve from time zero to the end of the dosing interval
- BW:
-
Body weight
- CL:
-
Clearance
- EMA:
-
European Medicines Agency
- ExPASy:
-
Expert protein analysis system
- Fab:
-
Antigen-binding fragment
- FDA:
-
Food and Drug Administration
- Fv:
-
Variable fragment
- GMFE:
-
Geometric mean fold error
- IV:
-
Intravenous
- mAb:
-
Monoclonal antibody
- MLR:
-
Multiple linear regression
- NHP:
-
Non-human primate
- PK:
-
Pharmacokinetics
- pI:
-
Isoelectric point
- PwFE:
-
Prediction within 0.8- to 1.2-fold errors
- SC:
-
Subcutaneous
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PZ designed the work, collected the data, conducted the analysis, and drafted the manuscript.
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PZ is a current employee of Daiichi Sankyo Inc.
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Zou, P. Predicting Human Bioavailability of Subcutaneously Administered Monoclonal Antibodies Using Non-human Primate Linear Clearance and Antibody Isoelectric Point. AAPS J 25, 53 (2023). https://doi.org/10.1208/s12248-023-00818-1
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DOI: https://doi.org/10.1208/s12248-023-00818-1