Simulation of monoclonal antibody pharmacokinetics in humans using a minimal physiologically based model.
AAPS J
; 16(5): 1097-109, 2014 Sep.
Article
em En
| MEDLINE
| ID: mdl-25004823
ABSTRACT
Compared to small chemical molecules, monoclonal antibodies and Fc-containing derivatives (mAbs) have unique pharmacokinetic behaviour characterised by relatively poor cellular permeability, minimal renal filtration, binding to FcRn, target-mediated drug disposition, and disposition via lymph. A minimal physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics of mAbs in humans was developed. Within the model, the body is divided into three physiological compartments; plasma, a single tissue compartment and lymph. The tissue compartment is further sub-divided into vascular, endothelial and interstitial spaces. The model simultaneously describes the levels of endogenous IgG and exogenous mAbs in each compartment and sub-compartment and, in particular, considers the competition of these two species for FcRn binding in the endothelial space. A Monte-Carlo sampling approach is used to simulate the concentrations of endogenous IgG and mAb in a human population. Existing targeted-mediated drug disposition (TMDD) models are coupled with the minimal PBPK model to provide a general platform for simulating the pharmacokinetics of therapeutic antibodies using primarily pre-clinical data inputs. The feasibility of utilising pre-clinical data to parameterise the model and to simulate the pharmacokinetics of adalimumab and an anti-ALK1 antibody (PF-03446962) in a population of individuals was investigated and results were compared to published clinical data.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Simulação por Computador
/
Anticorpos Monoclonais Humanizados
/
Modelos Biológicos
/
Anticorpos Monoclonais
Tipo de estudo:
Health_economic_evaluation
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article