title: Pharmacokinetic and pharmacodynamic interactions between palifermin and heparin.
abstract: Oral mucositis, a severe complication during chemo- and/or radiotherapy, is prevented with palifermin treatment, a recombinant human keratinocyte growth factor (KGF/FGF-7). The FGF family belongs to the larger family of heparin-binding growth factors. Because it has been shown that heparin modulates binding of KGF to the KGF receptor and subsequently affects cellular proliferation induced by the KGF mitogenic signal, it is critical to understand the drug-drug interactions between palifermin and heparin, particularly because of heparin's narrow therapeutic margin. Two studies were performed in healthy subjects to characterize the effect of palifermin on the pharmacodynamics of heparin (activated partial thromboplastin time) and evaluate the impact of heparin on the pharmacokinetics and pharmacodynamics (Ki67 staining of buccal mucosal tissue) of palifermin. Results demonstrated a pronounced pharmacokinetic interaction; heparin coadministration increased the palifermin AUC 4- to 5-fold and decreased its half-life by 40%-45%, suggesting an approximate 70%-80% decrease in palifermin clearance and volume of distribution. These changes in the pharmacokinetics of palifermin during coadministration of heparin, however, did not affect the pharmacodynamic effect of palifermin, or the anticoagulant activity of heparin, and did not lead to increased safety findings. Therefore, these results suggest that dose adjustments for heparin and palifermin are not warranted when administered concurrently.
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Bing-Bing
authors.initials: BB
authors.lastname: Yang
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Gillespie
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Smith
authors.affiliation: New Orleans Center for Clinical Research (NOCCR), University of Tennessee Medical Center, Knoxville, TN, USA.
authors.forename: William
authors.initials: W
authors.lastname: Smith
authors.affiliation: Swedish Orphan Biovitrum AB (publ) (Sobi), Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Lissmats
authors.affiliation: Swedish Orphan Biovitrum AB (publ) (Sobi), Stockholm, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Rudebeck
authors.affiliation: Swedish Orphan Biovitrum AB (publ) (Sobi), Stockholm, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Kullenberg
authors.affiliation: Swedish Orphan Biovitrum AB (publ) (Sobi), Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Olsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology*; D004347:Drug Interactions; D051523:Fibroblast Growth Factor 7 / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D009061:Mouth Mucosa / Q000378:metabolism; D010314:Partial Thromboplastin Time; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D019394:Ki-67 Antigen; D051523:Fibroblast Growth Factor 7; D006493:Heparin
keywords: drug-drug interaction; heparin; keratinocyte growth factor; palifermin; pharmacokinetics/pharmacodynamics