Pegylated Recombinant Consensus Interferon Variant(Chongqing Fujin Biological Medicine Co Ltd)

The aims of the study were to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of a novel, pegylated recombinant human consensus interferon‐α variant (PEG‐IFN‐SA) in healthy volunteers. A pharmacokinetic and pharmacodynamic comparison of PEG‐IFN‐SA and peginterferon‐α‐2a in healthy subjects was evaluated.

A randomized, dose‐escalating, single administration dose phase I clinical study was conducted. Thirty healthy subjects received PEG‐IFN‐SA as a single dose of 0.5–2.0 μg kg−1 by subcutaneous (s.c.) injection in four parallel groups. Eight subjects received peginterferon‐α‐2a as a single dose of 180 μg s.c.

The incidence rates of adverse events for PEG‐IFN‐SA and peginterferon‐α‐2a were 29 of 30 and 7 of 8, respectively. The adverse events for PEG‐IFN‐SA were mild to moderate and similar to those of peginterferon‐α‐2a. Within 168 h after injection, the mean values of maximal concentration and area under the plasma concentration–time curve from time of dosing to 168 h [AUC(0–168h)] for 2′,5′‐oligoadenylate, neopterin and β2‐microglobulin for PEG‐IFN‐SA at 1.5 μg kg−1 s.c. were similar to or higher than those for peginterferon‐α‐2a at a dose of 180 μg s.c. After s.c. injection of PEG‐IFN‐SA at 1.5 μg kg−1, the mean geometric mean values of plasma half‐life, time to maximal concentration, maximal concentration and AUC(0–168h) were 55.3 h, 26.9 h, 0.53 μg l−1 and 44.0 μg l−1 h, respectively.

The tolerance, pharmacokinetic and pharmacodynamic characteristics of PEG‐IFN‐SA support its administration by s.c. injection as a single dose of 1.5 μg kg−1 or at 2.0 μg kg−1 per week.

The study aims to characterize the pharmacokinetic, tissue distribution, excretion, and antiviral activity properties of a novel pegylated recombinant human consensus interferon-α variant (PEG-IFN-SA) following a single subcutaneous administration to monkeys, rats and guinea pigs. Studies included: (1) pharmacokinetic properties of PEG-IFN-SA and comparison with those of non-pegylated IFN-SA in rhesus monkeys and rats; (2) tissue distribution and urinary, fecal, and biliary excretion patterns of (125)I-PEG-IFN-SA in guinea pigs; and (3) antiviral activity assessment of PEG-IFN-SA in cynomolgus monkeys. The pegylated protein exhibited improved pharmacokinetic properties compared to IFN-SA in both monkeys and rats, with a 12-fold and 15-fold increase in elimination half-life, and a 100-fold and 10-fold decrease in serum clearance, as well as a 2.5-fold and 10-fold increase in the time to reach peak serum concentration, respectively. (125)I-PEG-IFN-SA was found to be distributed to most of the tissues examined and has character of targeting special distribution, and urinary appeared to be a major route for the excretion of PEG-IFN-SA in guinea pigs. Serum sample analysis from PEG-IFN-SA-treated monkeys showed dose-dependent antiviral activity for one week. These findings demonstrate that pegylation of IFN-SA results in more desirable pharmacokinetic properties, enhanced drug exposure and sustained-efficacy of in vivo antiviral action.