| Reference | [1]. Curr Drug Deliv. 2018;15(9):1230-1244. doi: 10.2174/1567201815666180620123347.<br />
Box-Behnken Design of Experiment Assisted Development and Optimization of Bendamustine HCl loaded Hydroxyapatite Nanoparticles.<br />
Thomas SC(1), Madaan T(1), Iqbal Z(1), Talegaonkar S(1)(2).<br />
Author information: (1)Nanoformulation Research Lab, Department of Pharmaceutics, School of Pharmaceutical Education & Research (formerly Faculty of Pharmacy), Jamia Hamdard, New Delhi-110062, India. (2)Department of Pharmaceutics, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, Sector 3, New Delhi-110017, India.<br />
BACKGROUND: Bendamustine HCl, an antineoplastic drug, has a very short life of about 40 minutes which necessitates administration of large doses which leads to increased side effects as well as costs. OBJECTIVE: The present work describes the fabrication, optimization, and evaluation of bioactive hydroxyapatite nanoparticles to achieve sustained delivery of bendamustine HCl. METHODS: Hydroxyapatite nanoparticles (NPs) were prepared by the wet chemical precipitation method by reacting a calcium and phosphate precursor and the reaction was optimized via Box-Behnken DOE. The drug was loaded on particles by physical adsorption. Various analytical studies were performed on the fabricated nanoparticles in addition to biodistribution studies to establish the physicochemical and biological characteristics of the designed formulation. RESULTS: pH of the reactant solution was found to have a more profound effect on the particle size and size distribution in comparison to reactant concentration. The particles were found to have a spherical morphology by SEM. Size of the blank and drug-loaded nanoparticles was found to be 130±20 nm by TEM. Energy Dispersive X-ray Spectroscopy (EDS) studies confirmed the presence of hydroxyapatite as the dominant phase while DSC studies indicated the presence of the drug in its amorphous form after its adsorption on NPs. Tissue distribution studies further suggested that the majority of drug concentration was released in blood rather than the other organs implying low organ toxicity. CONCLUSION: Bendamustine loaded hydroxyapatite nanoparticles were successfully optimized and fabricated. Favorable results were obtained in in vitro, in vivo, and analytical studies.<br />
DOI: 10.2174/1567201815666180620123347 PMID: 29929464 [Indexed for MEDLINE]<br />
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[2]. Ther Clin Risk Manag. 2008 Aug;4(4):727-32. doi: 10.2147/tcrm.s3158.<br />
Bendamustine HCL for the treatment of relapsed indolent non-Hodgkin's lymphoma.<br />
Weide R(1).<br />
Author information: (1)Praxisklinik für Hämatologie und Onkologie, Koblenz, Germany. [email protected]<br />
Bendamustine is an alkylating agent which also shows properties of a purine analog. Because of its unique mechanism of action it shows activity in relapsed indolent lymphomas which are resistant to alkylating agents, purine analogs, and rituximab. Bendamustine has a favorable toxicity profile causing no alopecia and only a moderate hematotoxicity and gastrointestinal toxicity. Combinations of bendamustine with mitoxantrone and rituximab and with rituximab alone have been shown to be highly active in relapsed/refractory indolent lymphomas and mantle cell lymphomas achieving long lasting complete remissions. Because of only moderate toxicity these combinations can be applied safely in elderly patients who can be treated in an outpatient setting.<br />
DOI: 10.2147/tcrm.s3158 PMCID: PMC2621381 PMID: 19209254<br />
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[3]. Cancer Chemother Pharmacol. 2010 Nov;66(6):1039-49. doi: 10.1007/s00280-010-1254-8. Epub 2010 Feb 6.<br />
Bendamustine pharmacokinetic profile and exposure-response relationships in patients with indolent non-Hodgkin's lymphoma.<br />
Owen JS(1), Melhem M, Passarell JA, D'Andrea D, Darwish M, Kahl B.<br />
Author information: (1)Cognigen Corporation, 395 South Youngs Road, Buffalo, NY 14221, USA.<br />
PURPOSE: The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin's lymphoma, and supported understanding of exposure-response relationships for efficacy and safety. METHODS: Bendamustine was administered as a 60-min 120 mg/m(2) intravenous infusion on days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined. RESULTS: Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t (1/2) (40 min) was considered the pharmacologically relevant (beta elimination) t (1/2) since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m(2) administration, except bendamustine C (max) was a significant (P value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics. CONCLUSIONS: The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t (1/2) and low concentrations of bendamustine observed by 12 h after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine C (max) increases.<br />
DOI: 10.1007/s00280-010-1254-8 PMCID: PMC2956859 PMID: 20140617 [Indexed for MEDLINE]<br />
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[4]. Clin Cancer Res. 2013 Nov 15;19(22):6313-21. doi: 10.1158/1078-0432.CCR-13-1848. Epub 2013 Oct 4.<br />
Bendamustine and rituximab in relapsed and refractory hairy cell leukemia.<br />
Burotto M(1), Stetler-Stevenson M, Arons E, Zhou H, Wilson W, Kreitman RJ.<br />
Author information: (1)Authors' Affiliations: Laboratories of Molecular Biology and Pathology, and Metabolism Branch, National Cancer Institute, NIH, Bethesda, Maryland.<br />
PURPOSE: To determine tolerability and for the first time explore efficacy of bendamustine-rituximab (BR) in multiply relapsed/refractory hairy cell leukemia (HCL), using two different dose levels of bendamustine. EXPERIMENTAL DESIGN: Patients with HCL with ≥2 prior therapies requiring treatment received rituximab 375 mg/m(2) days 1 and 15 plus bendamustine 70 (n = 6) or 90 (n = 6) mg/m(2), days 1 and 2, for six cycles at 4-week intervals. RESULTS: At 70 and 90 mg/m(2)/dose of bendamustine, overall response rate was 100%, with three (50%) and four (67%) complete remissions (CR) in each respective group. Minimal residual disease (MRD) was absent in 67% and 100% of CRs, respectively. All six without MRD remain in CR at 30 to 35 (median, 31) months of follow-up. Soluble CD22 and CD25 levels decreased with all responses, with median values decreasing from 17.7 and 42 ng/mL at baseline to undetectable and 2 ng/mL after CR, respectively (P < 0.001). Of 12 patients receiving 72 cycles of BR, the most common toxicities were hematologic, including thrombocytopenia (83%), lymphopenia (75%), leukopenia (58%), and neutropenia (42%). Grade III and IV hematologic toxicity included lymphopenia and thrombocytopenia (each 75%), leukopenia (58%), and neutropenia (25%). No significant dose-related differences were detected in response or toxicity. CONCLUSION: BR has significant activity in HCL. Bendamustine at either 70 or 90 mg/m(2)/dose was highly effective in multiply relapsed/refractory HCL and could be considered for achieving durable CRs without MRD in patients after failure of standard therapies. As it was not dose-limiting, 90 mg/m(2)/dose was chosen for future testing.<br />
DOI: 10.1158/1078-0432.CCR-13-1848 PMCID: PMC3861900 PMID: 24097860 [Indexed for MEDLINE]<br />
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[5]. J Cancer Res Clin Oncol. 2006 Feb;132(2):99-104. doi: 10.1007/s00432-005-0050-z. Epub 2005 Nov 15.<br />
Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukaemia (Binet stages B and C) requiring therapy.<br />
Lissitchkov T(1), Arnaudov G, Peytchev D, Merkle Kh.<br />
Author information: (1)National Center of Haematology and Transfusiology, 6 Plovdivsko Pole, 1746 Sofia, Bulgaria. [email protected]<br />
PURPOSE: Bendamustine hydrochloride, an anti-neoplastic agent with unique mechanism of action, is known to cause impressive remissions in relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukaemia (CLL). Optimal bendamustine dosing for CLL patients had not been finally established and a phase I/II study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of bendamustine. METHODS: The open-label, single-centre phase I/II study was conducted from March 2001 to September 2002 in Sofia, Bulgaria. The 15 study patients were extendedly pre-treated, but fludarabine-naive (3 female, 12 male, 47-72 years of age, 61 years on average). Bendamustine was given at a starting dose of 100 mg/m2 on days 1 and 2 every 3 weeks based on the previous results in lymphoma. RESULTS: Bendamustine was well tolerated in spite of heavy pre-treatment of the study participants. Toxicity corresponded to the known safety profile of bendamustine, with the exception of bilirubin elevation. The level of 110 mg/m2 was established as MTD. A bendamustine dose of 100 mg/m2 is the recommended dose for further clinical investigations. A 4-week interval is recommended to allow for sufficient recovery. Efficacy results confirmed powerful anti-neoplastic activity of bendamustine even in extendedly pre-treated CLL patients. Based on the remission criteria, nine patients were defined as responders (four CRs, two PR, three NC) and two patients as nonresponders to therapy. Four patients were not evaluable for response, because they had received less than three courses bendamustine. After a follow-up period of 15 months, the four patients with CR were still in remission. One patient with PR had relapsed, the other had ongoing response. CONCLUSIONS: Bendamustine is a very active and well-tolerated drug in patients with pre-treated and refractory CLL. Fludarabine-naivity of patients appears to markedly improve their bendamustine tolerability. First-line use of bendamustine is a safe option for CLL-patients requiring treatment, because bendamustine-owing to its unique pharmacodynamics-(1) is highly effective, (2) reasonably safe, and (3) does hardly produce cross-resistance against other anti-neoplastic drugs effective in this indication.<br />
DOI: 10.1007/s00432-005-0050-z PMID: 16292542 [Indexed for MEDLINE]
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