Pharmacokinetics and pharmacodynamics of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis in the randomized ADVANCE study

Br J Clin Pharmacol. 2015 Mar;79(3):514-22. doi: 10.1111/bcp.12521.

Abstract

Aims: 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.

Trial registration: ClinicalTrials.gov NCT00906399.

Keywords: interferon beta-1a; multiple sclerosis; pegylation.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Adjuvants, Immunologic / pharmacokinetics*
  • Adjuvants, Immunologic / pharmacology*
  • Adjuvants, Immunologic / therapeutic use
  • Adolescent
  • Adult
  • Aged
  • Antibodies, Neutralizing / blood
  • Area Under Curve
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Humans
  • Injections, Subcutaneous
  • Interferon-beta / administration & dosage
  • Interferon-beta / pharmacokinetics*
  • Interferon-beta / pharmacology*
  • Interferon-beta / therapeutic use
  • Male
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting / blood
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Neopterin / blood
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / pharmacokinetics*
  • Polyethylene Glycols / pharmacology*
  • Polyethylene Glycols / therapeutic use
  • Treatment Outcome
  • Young Adult

Substances

  • Adjuvants, Immunologic
  • Antibodies, Neutralizing
  • Polyethylene Glycols
  • Neopterin
  • Interferon-beta
  • peginterferon beta-1a

Associated data

  • ClinicalTrials.gov/NCT00906399