Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys
| Autor: | Joe X. H. Zhou, Gordon Moody, Bernardetta Nardelli, James H. Murray, Andrew Garcia, Cynthia Sung, Henrik S. Olsen, Blaire L. Osborn, Liubov Zaritskaya |
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| Rok vydání: | 2002 |
| Předmět: |
Male
Injections Subcutaneous Biological Availability Serum Albumin Human Pharmacology Biology Antiviral Agents Cell Line Subcutaneous injection Pharmacokinetics 2' 5'-Oligoadenylate Synthetase medicine Animals Humans RNA Messenger Dosing Serum Albumin Interferon-alpha Hepatitis B medicine.disease Human serum albumin Burkitt Lymphoma In vitro Bioavailability Macaca fascicularis Area Under Curve Pharmacodynamics COS Cells Injections Intravenous Molecular Medicine Female Cell Division medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 303:540-548 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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 foror =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 foror =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. |
| Databáze: | OpenAIRE |
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