Safety Pharmacology, Toxicology and Pharmacokinetic Assessment of Recombinant Human ω‐Interferon Produced from CHO‐SS Cells

Abstract

Human w-interferon (IFN-w) has been shown to be well-tolerated in man and to induce reductions of hepatitis C virus RNA levels in a series of human clinical trials. Here we provide an overview of our preclinical safety evaluation of the fully-glycosylated human IFN-w produced from CHO-SS cells that is currently being evaluated clinically. IFN-w was not associated with any biologically-relevant adverse effects in a series of 10 safety pharmacology experiments, in the Ames mutagenicity test, in the micronucleus test, or in intraarterial, intravenous, paravenous or subcutaneous local tolerance studies. Acute, subacute, subchronic and reproductive toxicity studies performed in cynomolgus monkeys and rats showed a toxicity profile similar to that of human a interferon (IFN-a). Except for the acute (single-dose) toxicology study, all of the other toxicity studies showed evidence for the formation of anti-IFN-w antibodies over time in the animals. These antibodies were found to neutralize IFN-w antiviral activity in vitro in a dose-dependent manner. The average pharmacokinetic parameters following a single subcutaneous dose of IFN-w in rabbits, rats and monkeys were determined and found to be similar to that of human IFN-a. These findings demonstrate that IFN-w has a safety profile consistent with that required for its use in man. IFN-w might be beneficial for the treatment of patients infected with hepatitis C virus who fail to respond to IFN-a or as a first-line treatment option.

Interferon-omega: Current status in clinical applications

“…Although IFN-ω has demonstrated promising antiviral activity against some viral infections in vivo and vitro, several factors could limit its antiviral efficacy, such as poor pharmacokinetics and a short half-life [36]. PEGylation, a covalent conjugation of nontoxic polyethylene glycol (PEG), has been demonstrated to improve the plasma half-life of a therapeutic protein and decrease its proteolytic sensitivity [37].…”

Effect of Co-administration of Tacrolimus on the Pharmacokinetics of Multiple Subcutaneous Administered Interferon-Alpha in Rats

“…The antibody produced by primary and/or secondary dose affects the PK of subsequent doses during multiple administrations. In fact, it has been reported that in multiple administration of human interferon omega in cynomolgus monkeys, the PK of a subsequent dose was modulated by antibodies elicited by multiple administration (2). Therefore, to compare the PK of same proteinic drug in the same experimental animal is difficult without methodological improvements.…”

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

“…It induces a SVR in patients infected with hepatitis C virus genotypes 1, 2 and 3 in clinical trials [128]. IFN-ω considerably reduces the production of HBsAg, comparable to the reduction obtained by treatment with IFN-α [29].…”