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

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.

© 2014 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Figures

Figure 1

Peginterferon beta-1a concentration-time profiles (A and B) and neopterin concentration−time profiles (C and D) from intensive subjects. Circles represent geometric mean concentration at week 4; squares represent geometric mean concentration at week 24; error bars indicate 95% confidence interval; dotted lines represent lower limit of quantitation, 31.3 pg ml−1 and 1.29 ng ml−1 for peginterferon beta-1a and neopterin, respectively

Figure 2

Correlation between peginterferon beta-1a AUC(0,τ) and demographic characteristics and creatinine clearance. AUC(0,τ) (mean of weeks 4 and 24) are shown for intensive subjects. Linear regression lines are shown with r2 values. BMI = body mass index; BSA = body surface area; CLcr = creatinine clearance estimated based on Cockcroft–Gault equation; WT = weight

Figure 3

Peginterferon beta-1a concentration−time profiles stratified by antibody status in patients with sparse sampling only. Data from every 2 weeks and every 4 weeks groups at weeks 4, 12, 24, 48, 56 and 84 were pooled. Open circles represent observed data; solid lines represent median values in specified time windows; dashed lines indicate lower limit of quantitation (LLOQ; 31.3 pg ml−1). Concentrations below LLOQ are shown as LLOQ

Figure 4

Pre-dose neopterin concentration in week 0, week 4 and week 24 for intensive subjects. Circles represent geometric mean concentration for the every 2 weeks group; squares represent geometric mean concentration for the every 4 weeks group; error bars indicate 95% confidence interval

Figure 5

Neopterin concentration−time profiles stratified by antibody status in patients with sparse sampling only. Data from every 2 weeks and every 4 weeks groups at weeks 4, 12, 24, 48, 56 and 84 were pooled. Open circles represent observed data; solid lines represent median values in specified time windows; dashed lines indicate lower limit of quantitation (LLOQ; 1.29 pg ml−1). Concentrations below LLOQ are shown as LLOQ