title: Pharmacokinetics and pharmacodynamics of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis in the randomized ADVANCE study.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneous peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS) in the phase 3 ADVANCE study (n = 1512).
  
  
  METHODS
  During year 1, patients were randomized (1:1:1) to placebo or peginterferon beta-1a 125 μg every 2 or 4 weeks. After year 1, patients randomized to placebo were re-randomized to 125 μg peginterferon beta-1a administered every 2 weeks or every 4 weeks for year 2. Patients randomized to peginterferon beta-1a in year 1 remained on the same dosing regimen in year 2. Intensive blood samples for PK and PD (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) measurements were collected from 44 patients pre-dosing and at intervals over 240 h post-dosing at weeks 4 and 24. Sparse samples were collected from all patients after each dosing at weeks 4, 12, 24, 56 and 84.
  
  
  RESULTS
  The PK profile of peginterferon beta-1a did not change over time or between dosing regimens. No accumulation was observed. Peak serum concentrations were reached 1-1.5 days post-dosing, with a mono-phasic decline and a median half-life of approximately 2-3 days. Dosing every 2 weeks provided approximately two-fold greater monthly cumulative area under the curve than every 4 weeks. Neopterin elevation was sustained for 10-14 days following each dose, indicating doubled cumulative duration of pharmacological activity for dosing every 2 weeks vs. every 4 weeks.
  
  
  CONCLUSIONS
  These PK/PD profiles potentially explain the enhanced efficacy of dosing every 2 weeks in patients with RRMS.
authors.affiliation: Biogen Idec Inc., Cambridge, MA, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.forename: Yue
authors.initials: Y
authors.lastname: Cui
authors.forename: Joleen
authors.initials: J
authors.lastname: White
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.forename: Aaron
authors.initials: A
authors.lastname: Deykin
authors.forename: Ivan
authors.initials: I
authors.lastname: Nestorov
authors.forename: Serena
authors.initials: S
authors.lastname: Hung
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000097:blood; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D016899:Interferon-beta / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D019798:Neopterin / Q000097:blood; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D011092:Polyethylene Glycols; D019798:Neopterin; D016899:Interferon-beta; C428112:peginterferon beta-1a
keywords: interferon beta-1a; multiple sclerosis; pegylation