ABSTRACT
Bendamustine hydrochloride (BDM) is approved in the United States to treat chronic lymphocytic leukemia and relapsed indolent B-cell non-Hodgkin lymphoma. The first formulation marketed in the United States (original BDM) was a lyophilized product requiring reconstitution prior to dilution to the final admixture. A liquid formulation of BDM was subsequently introduced that did not require reconstitution before dilution. Both formulations are administered as a 500 mL admixture with a recommended infusion time of 30 or 60 minutes for chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma, respectively. A newer liquid BDM formulation (rapid BDM) is a ready-to-dilute solution not requiring reconstitution that dilutes into an admixture of only 50 mL and can be safely administered in a shorter infusion time (10 minutes). Rapid BDM admixture also has longer stability at room temperature than both lyophilized and liquid BDM formulations (6 vs 2 to 3 hours). This phase 1, open-label, randomized, crossover (3-period, partially replicated) study, conducted in "end-of-life" cancer patients at 10 oncology centers in the United States, demonstrates that rapid BDM is bioequivalent to original BDM as determined by area under the curve. Expected differences in maximum plasma concentration and time to maximum plasma concentration were observed between study treatments, given the substantially shorter infusion time of rapid BDM. No clinically relevant differences in other evaluated pharmacokinetic parameters were found. Rapid BDM infusions were safe and tolerable for cancer patients in this study. The overall safety profiles of the 2 BDM formulations were comparable, with no new safety signals identified and no differences in infusion-related adverse events.
Subject(s)
Bendamustine Hydrochloride/adverse effects , Bendamustine Hydrochloride/pharmacokinetics , Adult , Aged , Aged, 80 and over , Area Under Curve , Bendamustine Hydrochloride/administration & dosage , Biological Availability , Chemistry, Pharmaceutical/methods , Cross-Over Studies , Female , Humans , Injection Site Reaction/etiology , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Male , Middle Aged , Therapeutic EquivalencyABSTRACT
The aim of this study was to investigate the fibroblast growth factor receptor 3 (FGFR3) mRNA cleavage by ribozymes targeting FGFR3, effect of growth inhibition and associated with mechanism on multiple myeloma (MM). We designated two ribozyme-expressing plasmids that target the FGFR3 genes, Rz52 and Rz32. In vitro catalytic activity of Rz52 and Rz32 in KMS11 cells decreased FGFR3 mRNA expression to 45% (p < 0.05) and 80% (p < 0.5), respectively, of that of the control. In vivo examination of the Rz52-transfected KMS11 clone showed that FGFR3 mRNA expression decreased to 20% (p < 0.05) of the control. In the Rz52-transfected H929 clone, FGFR3 mRNA decreased to 50% of the control. Protein expression of FGFR3 decreased to 70% of the parental KMS11 and H929 clones. DNA synthesis in the Rz52-transfected KMS11 clone decreased to 20% of that of the control, whereas the viability of cells decreased to 2% (p < 0.01) of that of the control. Ribozyme cleavage-associated increase in apoptosis of Rz52 KMS11 transfectants was twice that of the control. The inhibition of FGFR3 expression by ribozymes was associated with decreased vascular endothelial growth factor (VEGF) expression and upregulation of Flt-1 but not of the KDR receptor. Our data indicate that FGFR3 is an important cell survival and antiapoptotic factor for MM cells and that ribozyme-targeted downregulation of FGFR3 might be useful as a novel therapeutic intervention in MM characterized by t(4;14).
