Palifermin is a 140 amino acid protein with a molecular weight of 16.3 kilodaltons. It differs from endogenous human KGF in that the first 23 N-terminal amino acids have been deleted to improve protein stability.
KGF is a protein that targets epithelial cells by binding to specific cell-surface receptors thereby stimulating proliferation, differentiation, and upregulation of cytoprotective mechanisms (e.g. induction of antioxidant enzymes). Endogenous KGF is an epithelial cell specific growth factor which is produced by mesenchymal cells and is naturally upregulated in response to epithelial tissue injury.
Epithelial cell proliferation was assessed by Ki67 immunohistochemical staining in healthy subjects. A 3-fold or greater increase in Ki67 staining was observed in buccal biopsies from 3 of 6 healthy subjects given palifermin at 40 micrograms/kg/day intravenously for 3 days, when measured 24 hours after the third dose. Dose-dependent epithelial cell proliferation was observed 48 hours post-dosing in healthy subjects given single intravenous doses of 120 to 250 micrograms/kg.
The pharmacokinetics of palifermin were studied in healthy volunteers and patients with haematological malignancies. After single intravenous doses of 20 to 250 micrograms/kg (healthy volunteers) and 60 micrograms/kg (cancer patients), palifermin exhibited rapid extravascular distribution In patients with haematological malignancies mean Vss was 5 l/kg and mean clearance about 1300 ml/hour/kg with an average terminal half-life of approximately 4.5 hours. Approximately dose-linear pharmacokinetics were observed in healthy volunteers after single dose administration up to 250 micrograms/kg. No accumulation of palifermin occurred after 3 consecutive daily doses of 20 and 40 micrograms/kg (healthy volunteers) or 60 micrograms/kg (adult patients) or 40 to 80 micrograms/kg (paediatric patients). Inter-subject variability is high with a CV% of about 50% for CL and 60% for Vss.
No gender-related differences were observed in the pharmacokinetics of palifermin. Mild to moderate renal impairment (creatinine clearance 30-80 ml/min) did not influence palifermin pharmacokinetics. In patients with severe renal impairment (creatinine clearance <30 ml/min), clearance was decreased by 22% (n=5). In patients with end-stage renal disease (requiring dialysis) palifermin clearance was decreased by 10% (n=6). The pharmacokinetic profile in patients with hepatic insufficiency has not been assessed.
In a single dose study the clearance of palifermin was approximately 30% lower in 8 healthy subjects aged 66-73 years after a dose of 90 micrograms/kg than in younger subjects (≤65 years) after a dose of 180 micrograms/kg. Based on these limited data no recommendation on dose adjustment can be made.
In a small multiple-dose study in paediatric patients (1 to 16 years old) receiving 40, 60 or 80 micrograms/kg/day for 3 days pre- and post- HSCT, there was no effect of age on the pharmacokinetics of palifermin although a large variability was observed in the estimated parameters. Systemic exposure did not appear to increase with the dose.
Salient findings in toxicology studies in rat and monkey were generally attributable to the pharmacological activity of palifermin, specifically, proliferation of epithelial tissues.
In fertility/general reproductive toxicity studies in rats, palifermin treatment was associated with systemic toxicity (clinical signs and/or changes in body weight) and adverse effects on male and female reproductive/fertility parameters at doses greater than or equal to 300 micrograms/kg/day. No adverse effects on reproductive/fertility parameters were observed at doses of up to 100 micrograms/kg/day. These no observed adverse effect level (NOAEL) doses were associated with systemic exposures up to 2.5 times greater than anticipated clinical exposure.
In embryo/foetal development toxicity studies in rats and rabbits, palifermin treatment was associated with developmental toxicity (increased post-implantation loss, reduced litter size, and/or reduced foetal weight) at doses of 500 and 150 micrograms/kg/day, respectively. Treatment with these doses was also associated with maternal effects (clinical signs and/or changes in body weight/food consumption), suggesting that palifermin was not selectively toxic to development in either species. No adverse developmental effects were observed in rats and rabbits at doses of up to 300 and 60 micrograms/kg/day, respectively. These NOAEL doses were associated with systemic exposures (based on AUC) up to 9.7 and 2.1 times, respectively, anticipated clinical exposure. Peri- and postnatal development has not been studied.
Palifermin is a growth factor that primarily stimulates epithelial cells through the KGF receptor. Haematologic malignancies do not express the KGF receptor. However, patients treated with chemotherapy and/or radiotherapy are at higher risk of developing secondary tumours some of which may express KGF receptors, and theoretically, be stimulated by KGF receptor ligands. In a study to assess potential carcinogenicity in transgenic rasH2 mice, no treatment related increases in the incidence of neoplastic lesions were observed.
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