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.

Safety, Pharmacokinetics, and Efficacy of Palifermin in Children and Adolescents with Acute Leukemias Undergoing Myeloablative Therapy and Allogeneic Hematopoietic Stem Cell Transplantation: A Pediatric Blood and Marrow Transplant Consortium Trial

“…A few patients had a slower distribution phase, resulting in larger AUCs and thus lower clearance values than what was generally seen. The pattern resembles the one seen during co-administration of palifermin and heparin where decreased volume of distribution and clearance were postulated to be attributed to binding of palifermin to heparin in the central compartment and reduced cellular uptake of palifermin due to competing binding by heparin to the cell surface heparin sulfate proteoglycan [39]. The reason for this nontypical distribution pattern of palifermin in the present study, however, has not been possible to confirm.…”

Current trends in drug metabolism and pharmacokinetics

“…For example, palifermin is a truncated form of the endogenous fibroblast growth factor which contains the heparin-binding domains. Co-administration of palifermin with heparin was found to increase the systemic exposure to palifermin up to 5-fold 171 .…”

Drug Development of Therapeutic Monoclonal Antibodies

“…Heparin co-administration increased the palifermin area under the plasma concentration-time curve (AUC) 4-to 5-fold and decreased its half-life by 40-45 %, suggesting an approximately 70-80 % decrease in palifermin clearance and volume of distribution. However, these changes in the pharmacokinetics of palifermin during co-administration of heparin did not affect the pharmacodynamic effect of palifermin, or the anticoagulant activity of heparin, and did not lead to increased safety findings [90].…”