Cargando…

Translational Pharmacokinetic/Pharmacodynamic Modeling of Tumor Growth Inhibition Supports Dose‐Range Selection of the Anti–PD‐1 Antibody Pembrolizumab

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD‐1), has a manageable safety profile and robust clinical activity against advanced malignancies. The lowest effective dose for evaluation in further dose‐ranging studies was identified by developing a translational model fr...

Descripción completa

Detalles Bibliográficos
Autores principales: Lindauer, A, Valiathan, CR, Mehta, K, Sriram, V, de Greef, R, Elassaiss‐Schaap, J, de Alwis, DP
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270293/
https://www.ncbi.nlm.nih.gov/pubmed/27863176
http://dx.doi.org/10.1002/psp4.12130
Descripción
Sumario:Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD‐1), has a manageable safety profile and robust clinical activity against advanced malignancies. The lowest effective dose for evaluation in further dose‐ranging studies was identified by developing a translational model from preclinical mouse experiments. A compartmental pharmacokinetic model was combined with a published physiologically based tissue compartment, linked to receptor occupancy as the driver of observed tumor growth inhibition. Human simulations were performed using clinical pharmacokinetic data, literature values, and in vitro parameters for drug distribution and binding. Biological and mathematical uncertainties were included in simulations to generate expectations for dose response. The results demonstrated a minimal increase in efficacy for doses higher than 2 mg/kg. The findings of the translational model were successfully applied to select 2 mg/kg as the lowest dose for dose‐ranging evaluations.