Address correspondence to:
Prof. Avidan U. Neumann
The Mina and Everard Goodman Faculty of Life Sciences
Bldg 212, Rm 210
Ramat Gan 52900, Israel
Email: [email protected]
Abstract: Background: Using mathematical models, the pharmacodynamic properties of albinterferon alfa-2b (alb-IFN), a long-acting, recombinant protein comprising interferon alfa-2b genetically fused to human albumin, were analyzed. Methods/principal findings: Serum hepatitis C virus-RNA and alb-IFN levels were measured over 42 days in IFN-naïve patients with genotype 1 chronic hepatitis C who received 2 subcutaneous alb-IFN 900 µg (n = 12) or 1200 µg (n = 14) injections 14 days apart. An advanced viral dynamics model with antiviral effectiveness as a Hill response function of alb-IFN levels was fitted to the data to estimate pharmacokinetic, viral kinetic, and pharmacodynamic parameters. Antiviral response as a function of alb-IFN serum levels was determined by 90% effective concentration (EC90) and second-order sensitivity to changes in alb-IFN levels (Nhill coefficient). No significant differences between the 900 µg and 1200 µg groups were observed in viral kinetics or pharmacodynamics. In the combined groups (median values), a robust first-phase hepatitis C virus–RNA reduction (1.68 log10 IU/mL) preceded a rapid second-phase decline slope (0.48 log10IU/mL/wk). The alb-IFN EC90 was 4.31 log10 pg/mL, maximal antiviral quotient (maximal concentration/EC90) was 2.62, and inhibitory quotient (Day 14 concentration/EC90) was 1.14. Drug levels were > EC90 for a median 14 days, preventing rebound in most patients. Second-order sensitivity to changes in alb-IFN levels was low (Nhill = 1.0), leading to slower viral rebounds in the few patients with rebound. Conclusions/significance: Alb-IFN exhibited robust pharmacodynamic properties and maintained high antiviral effectiveness for a prolonged duration, supporting dosing at 2-week or 4-week intervals. These results suggest the potential of alb-IFN as a favorable choice of interferon alfa for combination therapy with the newly developed direct anti-hepatitis C virus agents.
Disclosure: Prof Rozenberg has received research grants from Human Genome Sciences. Prof Bain is a clinical investigator and consultant for Human Genome Sciences. Prof McHutchison has received research grants in an advisory capacity from Human Genome Sciences, Schering Plough, and Roche. Prof Pulkstenis and Prof Subramanian are employed by Human Genome Sciences. Prof Neumann is a consultant for and has received research grants from Human Genome Sciences and Roche. He is a member of the speakers’ bureaus for Human Genome Sciences, Roche, and Schering Plough.