Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems.
J Pharmacokinet Pharmacodyn
; 46(3): 287-304, 2019 06.
Article
em En
| MEDLINE
| ID: mdl-31037615
ABSTRACT
Guiding the dose selection for monoclonal antibody oncology drugs is often done using methods for predicting the receptor occupancy of the drug in the tumor. In this manuscript, previous work on characterizing target inhibition at steady state using the AFIR metric (Stein and Ramakrishna in CPT Pharmacomet Syst Pharmacol 6(4)258-266, 2017) is extended to include a "target-tissue" compartment and the shedding of membrane-bound targets. A new potency metric average free tissue target to initial target ratio (AFTIR) at steady state is derived, and it depends on only four key quantities the equilibrium binding constant, the fold-change in target expression at steady state after binding to drug, the biodistribution of target from circulation to target tissue, and the average drug concentration in circulation. The AFTIR metric is useful for guiding dose selection, for efficiently performing sensitivity analyses, and for building intuition for more complex target mediated drug disposition models. In particular, reducing the complex, physiological model to four key parameters needed to predict target inhibition helps to highlight specific parameters that are the most important to estimate in future experiments to guide drug development.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antineoplásicos Imunológicos
/
Anticorpos Monoclonais
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Pharmacokinet Pharmacodyn
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Canadá