title: Population-Based Pharmacokinetic and Exposure-Efficacy Analyses of Peginterferon Beta-1a in Patients With Relapsing Multiple Sclerosis.
abstract: Peginterferon beta-1a reduced annualized relapse rate as compared with placebo and was approved to treat multiple sclerosis patients. A population pharmacokinetic and an exposure-efficacy model were developed to establish the quantitative relationship between pharmacokinetics and annualized relapse rate. The pharmacokinetics was well described by a 1-compartment model with first-order absorption and linear elimination kinetics. Body mass index was the most significant covariate that impacted both clearance and volume of distribution, which in turn impacted area under the curve and maximum serum concentration. Cumulative monthly area under the curve and annualized relapse rate were best described by a Poisson-gamma (negative binomial) model, demonstrating that the improved efficacy of every-2-weeks dosing was driven by greater drug exposure. The results supported the superior efficacy of the every-2-week dosing regimen compared with the every-4-weeks dosing regimen.
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Hang
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Gilead Sciences Inc, Cambridge, MA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Shifang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Seddighzadeh
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Deykin
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Nestorov
mesh_terms: D000328:Adult; D019540:Area Under Curve; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D011092:Polyethylene Glycols; D016899:Interferon-beta; C428112:peginterferon beta-1a
keywords: annualized relapse rate; count data; interferon beta-1a; pegylation; pharmacometric analysis