Anti-neuropilin-1 (MNRP1685A): unexpected pharmacokinetic differences across species, from preclinical models to humans.
Pharm Res
; 29(9): 2512-21, 2012 Sep.
Article
em En
| MEDLINE
| ID: mdl-22707361
ABSTRACT
PURPOSE:
To compare the pharmacokinetics (PK) of MNRP1685A, a human monoclonal antibody (mAb) against neuropilin-1 (NRP1), in mice, rats, monkeys, and cancer patients from a Phase I study to model with parallel linear and nonlinear clearances.METHODS:
Binding characteristics of MNRP1685A in different species were evaluated using surface plasmon resonance technology. PK profiles of MNRP1685A after single and/or multiple doses in different species were analyzed using population analysis. PK parameters were compared across species.RESULTS:
MNRP1685A binds to NRP1 in all four species tested. Consistent with the wide expression of NRP1, MNRP1685A demonstrated pronounced non-linear PK over a wide dose range. PK profiles are best described by a two-compartment model with parallel linear and nonlinear clearances. Model-derived PK parameters suggest similar in-vivo target expression levels and binding affinity to target across all species tested. However, compared to typical human/humanized mAbs, non-specific clearance of MNRP1685A was faster in mice, rats, and humans (60.3, 19.4, and 8.5 ml/day/kg), but not in monkeys (3.22 ml/day/kg).CONCLUSIONS:
Monkey PK properly predicted the target-mediated clearance of MNRP1685A but underestimated its non-specific clearance in humans. This unique PK property warrants further investigation of underlying mechanisms.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neuropilina-1
/
Anticorpos Monoclonais
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article