title: Pharmacologic and pharmacokinetic profile of repifermin (KGF-2) in monkeys and comparative pharmacokinetics in humans.
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 microg/kg IV or 750 microg/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 microg/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.affiliation: Human Genome Sciences, Inc, Rockville, Maryland 20850, USA. cynthia_sung@hgsi.com
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sung
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Parry
authors.forename: Todd A
authors.initials: TA
authors.lastname: Riccobene
authors.forename: Angela
authors.initials: A
authors.lastname: Mahoney
authors.forename: Viktor
authors.initials: V
authors.lastname: Roschke
authors.forename: James
authors.initials: J
authors.lastname: Murray
authors.forename: Mi Li
authors.initials: ML
authors.lastname: Gu
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Glenn
authors.forename: Florence
authors.initials: F
authors.lastname: Caputo
authors.forename: Cindy
authors.initials: C
authors.lastname: Farman
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Odenheimer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C496463:FGF10 protein, human; D051526:Fibroblast Growth Factor 10; D011994:Recombinant Proteins; D005346:Fibroblast Growth Factors