Biological Disposition Of A Novel Pegylated Consensus Interferon

A novel pegylated consensus interferon （PEG-IFN-SA）, investigated in thispaper, is a biotech drug for the treatment of chronic hepatitis C virus infections.Thisstudy first evaluated the biological disposition of non-clinical and clinical pharmaco-kinetics （PK）/pharmacodynamics （PD） of PEG-IFN-SAIn this study, based on characteristic of biotech drugs, multiple quantitativebioanalytical methods, including radioimmunoassay （RIA）, enzyme linkedimmunosorbent assay （ELISA）, bioassay, and radioactive isotope trace assay, wereestablished and employed. The purpose of this series of studies was to characterize thepharmacokinetic, pharmacodynamic, tissue distribution, excretion, and antiviralefficacy properties, and PK-PD relationship of PEG-IFN-SA following a singlesubcutaneous administration to monkeys, rat, guinea pigs and healthy volunteers,thereby providing critical information for human health risk assessment. Studiesincluded:（1） pharmacokinetic properties of PEG-IFN-SA and comparison with thoseof non-pegylated consensus interferon （IFN-SA） in rhesus monkeys and rats;（2）antiviral activity assessment of PEG-IFN-SA in cynomolgus monkeys;（3） tissuedistribution and urinary, fecal, and biliary excretion patterns of¹²⁵I-PEG-IFN-SA inguinea pigs; and （4） pharmacokinetic and pharmacodynamic profiles of PEG-IFN-SAin healthy volunteers.The pegylated protein exhibited improved pharmacokinetic properties comparedto IFN-SA in both monkeys and rats, with a12-fold and15-fold increase inelimination half life, and a100-fold and10-fold decrease in serum clearance （CL）, aswell as a2.5-fold and10-fold increase in the time to reach peak serum concentration(T_max), respectively. In rats treated with PEG-IFN-SA following single s.c.administration at doses of7,14, and28μg/kg, a greater than proportional increase inboth Cmaxand AUC for PEG-IFN-SA was observed with increasing dose, while therate of clearance decreased. Both T_maxand t_1/2βdid not display markedly dosedependence. Compared with IFN-SA at an identical dose, AUC of PEG-IFN-SA wasapproximately8-fold greater, while Cmaxwas approximately half that of IFN-SA.Serum sample analysis from PEG-IFN-SA-treated monkeys at doses of10,30, and90μg/kg showed dose dependent antiviral activity for at least one week. ¹²⁵I-PEG-IFN-SA was found to be distributed to most of the tissues examined and hascharacter of targeting special distribution. The highest radioactivity levels weredetected in the spleen and kidney. Urinary appeared to be a major route for theexcretion of PEG-IFN-SA in guinea pigs.In healthy volunteers, the mean serum PEG-IFN-SA elimination half-life was51h. T_maxof PEG-IFN-SA occurred at a earlier time and clearance was greater relativeto Pegasys. The characteristic analysis of PK/PD suggested PEG-IFN-SA-inducedserum2’,5’-oligoadenylate synthetase （2’,5’-OAS） activity, Neopterin and β2microglobulin concentration, three classic biomarkers for PEG-IFN-SA pharmaco-dynamics, were enhanced with increasing drug concentration, and sustained-efficacyof in vivo antiviral action for at least one week. T_max（2,5-A），T_max（Neopterin）and T_max（β2M）ofthree classic biomarkers were achieved much later in comparison with T_maxof serumdrugs concentration. In additon, PEG-IFN-SA induced dose-depended increases inhuman serum2’,5’-OAS activity.These findings demonstrate that pegylation of IFN-SA results in more desirablepharmacokinetic and pharmacodynamic properties, prolonged biological half-life,decreased system clearance, enhanced drug exposure, reduced serum peak-to-troughconcentration ratio and increased in vivo duration of antiviral efficacy compared tounmodified IFN-SA.