Gene Modulatory Effects, Pharmacokinetics, and Clinical Tolerance of Interferon‐ α 1b: A Second Member of the Interferon‐ α Family

Interferon‐ α 1 (IFN‐ α 1), which may have a primary role in innate immunity, differs significantly in amino‐acid sequence from IFN‐ α 2, the only recombinant IFN‐ α with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5–270  μ g/m 2 of recombinant IFN‐ α 1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant ( P <0.01) dose and gene‐dependent increases of 2−10 fold occurred in IFN‐stimulated genes, including four (tumor necrosis factor‐related apoptosis‐inducing ligand, cig 5, p56, GEM) never previously identified as increased in patients; significant increases ( P <0.01) resulted at the lowest dose (1.5  μ g/m 2 ; 1.5 × 10 4 human antiviral units/m 2 ). Increases ( P <0.01) were sustainable for >4 weeks. Peak levels of IFN‐ α 1b were at 3 h; an increase of approximately eightfold in both C max and AUC occurred between 15  μ g/m 2 and 270  μ g/m 2 . Chronic toxicities of anorexia, weight loss, and fatigue were relatively uncommon. Eighteen patients were treated for >8 weeks; none experienced >grade 1 weight loss. Three patients at the highest dose developed grade 3 fatigue after ⩾3 months, which required dose reduction or discontinuation. Patient acceptability of fatigue defined a dose for initiation of Phase II trials, 270  μ g/m 2 . Six patients (five with renal cell carcinoma) had progression‐free survival for >1 year, including two who had partial responses. IFN‐ α 1b resulted in potent stimulation of IFN‐regulated genes and tumor regressions in renal cell carcinoma. Unique gene modulatory effects, when coupled with the moderate severity of side effects and a potentially central role in innate immunity, provide rationale for further clinical evaluation of IFN‐ α 1 in virus infections and cancer. Clinical Pharmacology & Therapeutics (2007) 81 , 354–361. doi: 10.1038/sj.clpt.6100081