Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case study.
MAbs
; 15(1): 2156317, 2023.
Article
em En
| MEDLINE
| ID: mdl-36524835
ABSTRACT
Receptor occupancy assays applied in clinical studies provide insights into pharmacokinetic-pharmacodynamic relationships for therapeutic antibodies. When measured by different assays, however, receptor occupancy results can be controversial, as was observed for nivolumab, a monoclonal antibody targeting programmed cell death 1 (PD-1) receptor. We suggested an explanation of results obtained and a mechanistic approach based on specific features of the receptor occupancy assays measurement of the free or bound receptor, normalized to the baseline or at each time point. The approach was evaluated against controversial clinical data on PD-1 receptor occupancy by nivolumab. It was shown that receptor occupancy measured by different assays might vary substantially if the internalization rate of the bound receptor is higher than the rate of degradation of the free receptor. Equations proposed in this work can be applied in quantitative systems pharmacology models to describe target receptor occupancy by different therapeutic antibodies.
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Base de dados:
MEDLINE
Assunto principal:
Nivolumabe
/
Farmacologia em Rede
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article