title: Population Pharmacokinetics and Target Engagement of Natalizumab in Patients With Multiple Sclerosis.
abstract: Natalizumab (humanized immunoglobulin G4 antibody targeting alpha-4 integrins) is a highly efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) that has been in clinical use since 2006. However, natalizumab pharmacokinetic (PK) characteristics and concentration alpha-4 integrin saturation relationships have not been well described in the scientific literature. Therefore, clinical data from 11 studies were pooled and analyzed to characterize the PK and pharmacodynamic (PD) properties of natalizumab in RRMS subjects. Natalizumab PK was best described using a 2-compartment model with linear first-order and Michaelis-Menten elimination. Subcutaneous absorption of natalizumab was characterized using first-order absorption with lag time. The relationship between natalizumab concentration and alpha-4 integrin saturation (PD) was best described by a direct response model with a sigmoidal effect on alpha-4 integrin saturation mediated by a maximum effect relationship with natalizumab concentrations. Covariate analysis showed that body weight, product formulations, and the presence of antinatalizumab antibodies were the main covariates affecting natalizumab PK, whereas age and formulations affected PD. The use of simulations based on a pharmacokinetic-pharmacodynamic model showed that covariates, although statistically significant, are not expected to have any clinical impact at the approved clinical dosing regimen of natalizumab (300 mg once every 4 weeks).
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Kumar Kandadi
authors.initials: KK
authors.lastname: Muralidharan
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Kuesters
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Plavina
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Meena
authors.initials: M
authors.lastname: Subramanyam
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Mikol
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Sreeja
authors.initials: S
authors.lastname: Gopal
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Nestorov
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D039001:Integrin alpha Chains / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D000069442:Natalizumab / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D039001:Integrin alpha Chains; D000069442:Natalizumab
keywords: alpha-4 integrin; alpha-4 integrin saturation; multiple sclerosis; natalizumab; population pharmacokinetics