Phase I study of the tolerability and pharmacokinetics of palifermin in children undergoing allogeneic hematopoietic stem cell transplantation.
ABSTRACT The maximum tolerated dose of palifermin, a keratinocyte growth factor, in children is not known, and its pharmacokinetics in this population has not been well studied. This is a phase I study of palifermin was designed to evaluate its tolerability at doses of 40, 60, and 90 μg/kg/day in children age 2-18 years of age, receiving a myeloablative preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT). In each cohort, palifermin was given for 3 consecutive days before the preparative regimen and for 3 days after the stem cell infusion. Twelve patients were enrolled. Palifermin 90 μg/kg/day was tolerated in 6 patients without dose-limiting toxicity. All patients had at least 1 adverse event, mostly National Cancer Institute grade 1 or 2 severity. Skin rash, grade 2 or lower, was the most common adverse event, seen in 67% of patients. Only 3 patients (25%) had mucositis. The area under the concentration-time curve increased proportionally to the dose, and approximately 97% of palifermin exposure occurred in the first 24 hours after administration. Palifermin clearance increased linearly with body weight, supporting dosing by body weight. The mean clearance was 1893 mL/hour/kg, and it did not change significantly between administration of the first and last doses (P = .80). The mean elimination half-life was 4.6 hours. Our data show that palifermin was tolerated at a dose of 90 μg/kg/day, and exhibits linear pharmacokinetics in children undergoing allogeneic HSCT.
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ABSTRACT: To investigate the effects of keratinocyte growth factor (KGF) on the structure of the stratified squamous epithelium of the tongue, buccal mucosa and oesophagus of normal and irradiated mice. Female BDF1 mice were exposed to total body irradiation from a caesium source. The irradiated mice and normal, unirradiated mice were injected with 5 mg/kg per day KGF or vehicle. Thickness and proliferation in the epithelium were measured. KGF caused epithelial thickening of the non-keratinized layers in oral epithelium in normal mice. It increased the number of nucleated layers and influenced differentiation of post-mitotic cells in the upper layers by increasing the size and number of keratohyalin granules, and the number of desmosomes. Single and fractionated doses of radiation caused inhibition of proliferation as detected by markedly reduced BrdU incorporation following exposure, followed by epithelial atrophy. KGF treatment of mice reversed the inhibition of proliferation and atrophy that occurred in control irradiated mice. These data show that KGF reverses epithelial atrophy in mouse oral cavity caused by irradiation and suggest that KGF may be useful for the treatment of mucositis of the upper aerodigestive tract of patients treated with aggressive regimens of radiation therapy.International Journal of Radiation Biology 06/1999; 75(5):609-20. · 1.90 Impact Factor
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ABSTRACT: The expression of the human Ki-67 protein is strictly associated with cell proliferation. During interphase, the antigen can be exclusively detected within the nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. The fact that the Ki-67 protein is present during all active phases of the cell cycle (G(1), S, G(2), and mitosis), but is absent from resting cells (G(0)), makes it an excellent marker for determining the so-called growth fraction of a given cell population. In the first part of this study, the term proliferation marker is discussed and examples of the applications of anti-Ki-67 protein antibodies in diagnostics of human tumors are given. The fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) is often correlated with the clinical course of the disease. The best-studied examples in this context are carcinomas of the prostate and the breast. For these types of tumors, the prognostic value for survival and tumor recurrence has repeatedly been proven in uni- and multivariate analysis. The preparation of new monoclonal antibodies that react with the Ki-67 equivalent protein from rodents now extends the use of the Ki-67 protein as a proliferation marker to laboratory animals that are routinely used in basic research. The second part of this review focuses on the biology of the Ki-67 protein. Our current knowledge of the Ki-67 gene and protein structure, mRNA splicing, expression, and cellular localization during the cell-division cycle is summarized and discussed. Although the Ki-67 protein is well characterized on the molecular level and extensively used as a proliferation marker, the functional significance still remains unclear. There are indications, however, that Ki-67 protein expression is an absolute requirement for progression through the cell-division cycle.Journal of Cellular Physiology 04/2000; 182(3):311-22. · 4.22 Impact Factor
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ABSTRACT: 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. Prospective, open-label pharmacokinetic study. University-affiliated hematology and oncology center. 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. 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. 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. 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.Pharmacotherapy 10/2007; 27(10):1353-60. · 2.31 Impact Factor