RESUMEN
STUDY OBJECTIVE: To assess the pharmacokinetic profile of palifermin after intravenous dosing with either a collapsed dose of 180 microg/kg/day for 1 day or a standard dose of 60 microg/kg/day for 3 days, before and after myeloablative chemoradiotherapy and peripheral blood progenitor cell (PBPC) transplantation. DESIGN: Prospective, open-label pharmacokinetic study. SETTING: University-affiliated hematology and oncology center. PATIENTS: Twenty-five adult patients with hematologic malignancies receiving myeloablative therapy; 13 were in the standard-dose group, and 12 were in the collapsed-dose group. INTERVENTION: Patients received total-body irradiation (study days -8 to -5), etoposide (day -4), cyclophosphamide (day -2), and PBPC transplantation (day 0). Standard-dose palifermin was administered on days -11, -10, -9, 0, 1, and 2; collapsed-dose palifermin was administered on days -11 and 0. MEASUREMENTS AND MAIN RESULTS: Baseline demographic and clinical characteristics were recorded. Blood samples were obtained for pharmacokinetic assessment, presence of palifermin antibodies, and routine chemistry and hematology panels. Adverse events were documented daily. For both dosing groups, palifermin concentrations declined rapidly (>or= 98%) in the first 30 minutes and increased slightly between 1 and 4 hours after dosing, with a terminal decay phase. For standard-dose palifermin, mean values for area under the serum concentration-time curve (AUC) were within 15% between doses 1 and 3 and within 1% between doses 1 and 4. For collapsed-dose palifermin, mean AUC values and other pharmacokinetic parameters were within 2% between doses 1 and 2. Mean AUC on days -11 and 0 were approximately 4-fold higher for collapseddose palifermin than for standard-dose palifermin. Both dosing regimens were well tolerated. CONCLUSIONS: Our results were consistent with approximately dose-linear pharmacokinetics for the two dosing regimens, with no observed accumulation. A randomized, controlled study is warranted to assess the safety and efficacy of collapsed-dose palifermin, which may provide a more convenient administration schedule.
Asunto(s)
Factor 7 de Crecimiento de Fibroblastos/farmacocinética , Neoplasias Hematológicas/terapia , Trasplante de Células Madre de Sangre Periférica , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Área Bajo la Curva , Terapia Combinada , Diarrea/inducido químicamente , Fraccionamiento de la Dosis de Radiación , Relación Dosis-Respuesta a Droga , Exantema/inducido químicamente , Femenino , Factor 7 de Crecimiento de Fibroblastos/administración & dosificación , Factor 7 de Crecimiento de Fibroblastos/efectos adversos , Semivida , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/radioterapia , Humanos , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Náusea/inducido químicamente , Factores de Tiempo , Irradiación Corporal Total/métodosRESUMEN
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.