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

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.