Pharmacy & Therapeutics - February 2009 - (Page 73)

DRUG FORECAST Bendamustine (Treanda) For Chronic Lymphocytic Leukemia A Brief Overview Hoyee Leong, PhD, and Mar y Ellen Bonk, PharmD INTRODUCTION Bendamustine HCl (Treanda, Cephalon, Inc.) is an intravenously administered alkylating agent that was approved by the FDA following a priority review for treating patients with chronic lymphocytic leukemia (CLL). The American Cancer Society estimated that more than 15,000 new cases of CLL would be diagnosed in the U.S. and that approximately 4,400 people would die of CLL during 2008.1 Bendamustine was approved for the treatment of CLL on the basis of a randomized, international, multicenter, open-label phase 3 study that compared the drug with chlorambucil (Leukeran, GlaxoSmithKline).2 Bendamustine has demonstrated clinical activity against various cancers, including non-Hodgkin’s lymphoma (NHL),3,4 multiple myeloma,5,6 breast cancer,7 small-cell lung cancer,8,9 and other solid tumors.10,11 The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology for NHL to include bendamustine as a single agent for the first-line therapy in patients with CLL. For second-line therapy, it can be used as a single agent or in combination with rituximab (Rituxan, Genentech/ Biogen Idec). Although bendamustine is currently approved only for the treatment of CLL, the guidelines also include it as an option for the second-line therapy for follicular lymphoma and mantle-cell lymphoma with a category 2B designation with or without rituximab.12 Bendamustine was granted orphan Dr. Leong is a Senior Research Specialist in Drug Information and Technology Assessment and Dr. Bonk is Manager of the Drug Information Group at the University HealthSystem Consortium in Oak Brook, Illinois. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi & Associates in New York, New York. drug status in 2007 and was approved by the FDA on March 20, 2008.13 On October 31, 2008, the FDA approved bendamustine for treating indolent B-cell NHL that progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.14 CHEMISTRY AND PHARMACOLOGY Bendamustine is a bifunctional derivative of mechlorethamine with a nitrogen mustard moiety and a benzimidazole ring. The nitrogen mustard group is an alkylating agent that dissociates into electrophilic alkyl groups that form covalent bonds with electron-rich nucleophilic moieties, including single-stranded and double-stranded DNA. Although the exact mechanism of action is unknown, the covalent linkage with DNA can lead to cell death in both quiescent and dividing cells.15 In preclinical studies, bendamustine displayed a unique profile compared with other alkylating agents; it exhibits several mechanisms of action, including induction of cell necrosis and apoptosis, activation of DNA repair by base excision, and inhibition of mitotic checkpoints.16 over a concentration of 10 to 100 mcg/ mL. The primary route of metabolism occurs via hydrolysis into inactive metabolites. In addition, two active metabolites, M3 and M4, are formed by hepatic cytochrome P450 1A2 at 1/10 and 1/100, respectively, the concentration of the parent compound. M3 and M4 are unlikely to exert significant pharmacological effect. Bendamustine is cleared at a rate of approximately 700 mL/minute, and it is eliminated primarily in the feces (90%). Its mean elimination half-life is 40 minutes.17 In preliminary reports, no pharmacokinetic differences were noted in terms of age or mild hepatic or renal sufficiency.17 No differences in pharmacodynamic parameters were observed in studies of the following patients who received bendamustine 120 mg/m2: • patients with renal impairment (N = 31) and a creatinine clearance (CrCl) of 40 to 80 mL/minute or with mild hepatic impairment (N = 26) • patients with a total bilirubin count at or below the upper limit of normal (ULN) • patients with aspartate aminotransferase (AST) levels of 1 to 2.5 times the ULN or higher or with alanine aminotransferase (ALT) levels of 1 to 5 times the ULN or higher Because these results are limited, however, caution should still be used in those patients with renal or hepatic insufficiency.17 Although the effect of race on pharmacokinetics has not been established, a study of six Japanese subjects indicated that bendamustine exposure was 40% higher than in non-Japanese subjects. Whether the observed difference significantly affects safety or efficacy in such patients remains unknown.17 PHARMACOKINETICS Peak plasma concentrations of bendamustine following a single intravenous (IV) administration (100 mg/m2) are achieved at the end of a one-hour infusion.17 Bendamustine has a mean steadystate volume of distribution of 25 L and is 94% to 96% bound to serum plasma proteins, primarily albumin, with minimal likelihood of displacement by other highly protein-bound drugs.17,18 Bendamustine is distributed freely in blood, with a blood-to-plasma concentration ratio ranging from 0.84 to 0.86 Disclosure: The authors have no commercial or financial relationships to disclose with regard to this article. Vol. 34 No. 2 • February 2009 • P&T® 73

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Pharmacy & Therapeutics - February 2009 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Pushing an Expanded Role for Pharmacists Better Asthma Management with Advanced Technology Pharmaceutical Approval Update 58th Annual Meeting, American Society of Human Genetics, 2008 American Society of Hematology, 50th Annual Meeting and Exposition 2008 San Antonio Breast Cancer Symposium Stahl’s Essential Psychopharmacology, 3rd Edition Author Guidelines

Pharmacy & Therapeutics - February 2009

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