Pharmacokinetics, pharmacodynamics, and safety assessment of palifermin (rHuKGF) in healthy volunteers.

Background: Palifermin is a recombinant human keratinocyte growth factor approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies who received myelotoxic therapy requiring hematopoietic stem cell support.

Methods: This randomized, double-blind, placebo-controlled study investigated the pharmacokinetics, pharmacodynamics, and safety of palifermin in healthy volunteers after single, escalating doses (60 to 250 mug/kg). Pharmacodynamic measurements (Ki67 staining) assessing buccal mucosal epithelial proliferation were performed at baseline and at 48 or 72 hours after dosing.

Results: Exposure to palifermin increased approximately dose proportionally, with a 3-fold increase observed for a 4-fold increase in dose. Palifermin concentrations decreased sharply during the first 0.5 to 1.5 hours after dosing, slightly increased or plateaued between 1.5 and 6 hours, and subsequently decreased. The overall mean systemic clearance and volume of distribution at steady state were 590 mL/h/kg and 2000 mL/kg, respectively. The mean half-life ranged from 4.5 to 6 hours across the dose levels. The mean and SD ratio of Ki67 staining at 48 hours after dosing to baseline was 1.19 (0.24) for placebo, 2.02 (0.60) for 60 mug/kg, 3.04 (1.13) for 120 mug/kg, and 4.66 (0.77) for 250 mug/kg-treated groups.

Conclusion: Palifermin exhibited linear pharmacokinetics and caused dose-dependent epithelial proliferation.