Pharmacologic and pharmacokinetic profile of repifermin (KGF-2) in monkeys and comparative pharmacokinetics in humans
Journal Title: The AAPS Journal - Year 2002, Vol 4, Issue 2
Abstract
Repifermin (truncated, recombinant human keratinocyte growth factor-2, KGF-2) was evaluated in cynomolgus monkeys and healthy humans during a phase 1 trial. Monkeys received vehicle or repifermin at 20, 75, or 200 μg/kg IV or 750 μg/kg subcutaneous (SC) daily for 29 days. Clinical observations were made during the entire dosing period. Gross and microscopic changes were assessed at necropsy. Pharmacokinetic parameters and immunogenicity were evaluated in these monkeys and in humans, following a single or 7 daily IV bolus injections of 1, 5, 25, or 50 μg/kg repifermin. In monkeys, repifermin was well tolerated, and histologic evaluation demonstrated dose-dependent, reversible thickening of the mucosa throughout the alimentary tract, except for the stomach. In the alimentary tract tissues, nonepithelial tissues were not affected, indicating a specificity of repifermin for epithelial cells. Pharmacokinetics in both monkeys and humans were dose proportional, showed lack of drug accumulation with repeated daily dosing, and were characterized by high volumes of distribution and clearance rates, indicating substantial tissue binding and metabolism. Repifermin was not markedly immunogenic following multiple daily IV injections in either species. Serum repifermin concentrations in humans were comparable to those attained in monkeys that produced significant pharmacological effects on epithelial cells in the alimentary tract. These findings provide additional support for the ongoing clinical development of repifermin for diseases involving epithelial injury.
Authors and Affiliations
Cynthia Sung, Tom J. Parry, Todd A. Riccobene, Angela Mahoney, Viktor Roschke, James Murray, Mi Li Gu, Jeffrey K. Glenn, Florence Caputo, Cindy Farman, Daniel J. Odenheimer
Keywords
Related Articles
- EP ID EP681998
- DOI 10.1208/ps040206
- Views 89
- Downloads 0
The kinetics of thiol-mediated decomposition of S-nitrosothiols
The reaction of sulfhydryl (SH)-containing molecules (thiols) with S-nitrosothiols (RSNO) has been shown to be of biological importance. Biologically or therapeutically relevant thiols generally have a pKa value ranging...
Inhibitors of the FcRn:IgG Protein–Protein Interaction
The neonatal Fc receptor, FcRn, is responsible for controlling the half-life of IgG antibodies. As a result, inhibitors of FcRn have been investigated as a possible way to modulate IgG half-lives. Such inhibitors could h...
Intranasal Delivery of Exendin-4 Confers Neuroprotective Effect Against Cerebral Ischemia in Mice
The online version of this article (doi:10.1208/s12248-015-9854-1) contains supplementary material, which is available to authorized users.
An Investigation into the Utility of a Multi-compartmental, Dynamic, System of the Upper Gastrointestinal Tract to Support Formulation Development and Establish Bioequivalence of Poorly Soluble Drugs
In recent years mechanical systems have been developed that more closely mimic the full dynamic, physical and biochemical complexity of the GI Tract. The development of these complex systems raises the possibility that t...
Pharmacodynamic Studies to Demonstrate Bioequivalence of Oral Inhalation Products
In the session on “Pharmacodynamic studies to demonstrate efficacy and safety”, presentations were made on methods of evaluating airway deposition of inhaled corticosteroids and bronchodilators, and syste...