title: Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys.
abstract: Interferon-alpha (IFN-alpha) is indicated for the treatment of certain viral infections including hepatitis B and C, and cancers such as melanoma. The short circulating half-life of unmodified IFN-alpha makes frequent dosing (daily or three times weekly) over an extended period (6-12 months or more) necessary. To improve the pharmacokinetics of IFN-alpha and decrease dosing frequency, IFN-alpha was fused to human serum albumin producing a new protein, Albuferon. In vitro comparisons of Albuferon and IFN-alpha showed similar antiviral and antiproliferative activities, although Albuferon was less potent on a molar basis than IFN-alpha. Pharmacokinetic and pharmacodynamic properties of the fusion protein were enhanced in monkeys. After a single intravenous injection (30 microg/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 microg/kg subcutaneous injection, apparent clearance (clearance divided by bioavailability) was 1.4 ml/h/kg, the terminal half-life was 93 h, and bioavailability was 64%. The rate of clearance of Albuferon was approximately 140-fold slower, and the half-life 18-fold longer, than for IFN-alpha given by the subcutaneous route in other monkey studies. Sera from Albuferon-treated monkeys demonstrated dose-related antiviral activity for > or =8 days based on an in vitro bioassay, whereas antiviral activity from IFN-alpha-treated animals was only slightly elevated relative to vehicle on day 0. Significant increases in 2',5'-oligoadenylate synthetase mRNA relative to IFN-alpha- or vehicle-treated animals were maintained for > or =10 days after subcutaneous dosing. The improved pharmacokinetics of Albuferon are accompanied by an improved pharmacodynamic response suggesting that Albuferon may offer the benefits of less frequent dosing and a potentially improved efficacy profile compared with IFN-alpha.
authors.affiliation: Human Genome Sciences, Inc., 9410 Key West Avenue, Rockville, MD 20850, USA. blaire_osborn@hgsi.com
authors.forename: Blaire L
authors.initials: BL
authors.lastname: Osborn
authors.forename: Henrik S
authors.initials: HS
authors.lastname: Olsen
authors.forename: Bernardetta
authors.initials: B
authors.lastname: Nardelli
authors.forename: James H
authors.initials: JH
authors.lastname: Murray
authors.forename: Joe X H
authors.initials: JX
authors.lastname: Zhou
authors.forename: Andrew
authors.initials: A
authors.lastname: Garcia
authors.forename: Gordon
authors.initials: G
authors.lastname: Moody
authors.forename: Liubov S
authors.initials: LS
authors.lastname: Zaritskaya
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sung
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000037:antagonists & inhibitors; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D002051:Burkitt Lymphoma / Q000473:pathology; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D012709:Serum Albumin; D000075462:Serum Albumin, Human
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012333:RNA, Messenger; D012709:Serum Albumin; C473631:albuferon; D015088:2',5'-Oligoadenylate Synthetase; D000075462:Serum Albumin, Human