Gene modulatory effects, pharmacokinetics, and clinical tolerance of interferon-alpha1b: a second member of the interferon-alpha family.
Gene modulatory effects, pharmacokinetics, and clinical tolerance of interferon-alpha1b: a second member of the interferon-alpha family.
复制标题
干扰素-α1b 的基因调节作用、药代动力学和临床耐受性：干扰素-α 家族的第二个成员。
DOI：
10.1038/sj.clpt.6100081
复制
发表时间：
2007
影响因子：
6.7
通讯作者：
Borden,EC
中科院分区：
文献类型：
--
作者：
Masci,P;Olencki,T;Wood,L;Rybicki,L;Jacobs,B;Williams,B;Faber,P;Bukowski,R;Tong,K;Borden,EC
Interferon‐α1 (IFN‐α1), which may have a primary role in innate immunity, differs significantly in amino‐acid sequence from IFN‐α2, the only recombinant IFN‐αwith substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5–270μg/m2of recombinant IFN‐α1b. 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 (1.5μg/m2; 1.5 × 104human antiviral units/m2). Increases (P<0.01) were sustainable for >4 weeks. Peak levels of IFN‐α1b were at 3 h; an increase of approximately eightfold in bothCmaxand AUC occurred between 15μg/m2and 270μg/m2. 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, 270μg/m2. Six patients (five with renal cell carcinoma) had progression‐free survival for >1 year, including two who had partial responses. IFN‐α1b 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‐α1 in virus infections and cancer.Clinical Pharmacology & Therapeutics(2007)81, 354–361. doi:10.1038/sj.clpt.6100081
