Gene Modulatory Effects, Pharmacokinetics, and Clinical Tolerance of Interferon‐α1b: A Second Member of the Interferon‐α Family
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‐α with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5–270 μg/m2 of recombinant...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 2007-03, Vol.81 (3), p.354-361 |
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| creator | Masci, P Olencki, T Wood, L Rybicki, L Jacobs, B Williams, B Faber, P Bukowski, R Tong, K Borden, E C |
| description | 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‐α with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5–270 μg/m2 of recombinant IFN‐α1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant (Pgrade 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 μg/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 |
| doi_str_mv | 10.1038/sj.clpt.6100081 |
| format | Article |
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Clinical Pharmacology & Therapeutics (2007) 81, 354–361. doi:10.1038/sj.clpt.6100081</description><subject>Biological and medical sciences</subject><subject>Medical sciences</subject><subject>Pharmacology. 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Drug treatments</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Masci, P</creatorcontrib><creatorcontrib>Olencki, T</creatorcontrib><creatorcontrib>Wood, L</creatorcontrib><creatorcontrib>Rybicki, L</creatorcontrib><creatorcontrib>Jacobs, B</creatorcontrib><creatorcontrib>Williams, B</creatorcontrib><creatorcontrib>Faber, P</creatorcontrib><creatorcontrib>Bukowski, R</creatorcontrib><creatorcontrib>Tong, K</creatorcontrib><creatorcontrib>Borden, E C</creatorcontrib><collection>Pascal-Francis</collection><collection>CrossRef</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Masci, P</au><au>Olencki, T</au><au>Wood, L</au><au>Rybicki, L</au><au>Jacobs, B</au><au>Williams, B</au><au>Faber, P</au><au>Bukowski, R</au><au>Tong, K</au><au>Borden, E C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gene Modulatory Effects, Pharmacokinetics, and Clinical Tolerance of Interferon‐α1b: A Second Member of the Interferon‐α Family</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><date>2007-03</date><risdate>2007</risdate><volume>81</volume><issue>3</issue><spage>354</spage><epage>361</epage><pages>354-361</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>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‐α with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5–270 μg/m2 of 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 (1.5 μg/m2; 1.5 × 104 human 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 both Cmax and AUC occurred between 15 μg/m2 and 270 μg/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, 270 μg/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.
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| subjects | Biological and medical sciences Medical sciences Pharmacology. Drug treatments |
| title | Gene Modulatory Effects, Pharmacokinetics, and Clinical Tolerance of Interferon‐α1b: A Second Member of the Interferon‐α Family |
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