December 2012, Vol 4 No 1

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History and Characterization of Bendamustine

This is the first article in a 4-part series on bendamustine. This article describes the history and characterization of bendamustine. Subsequent articles will discuss the efficacy and safety of bendamustine in registration studies and describe ongoing clinical investigations of bendamustine.

Bendamustine is a bifunctional chemotherapeutic agent with both alkylating and antimetabolite (purine analog) properties, which are discussed in more detail below.1,2 Ben­damustine is known by the trade names Treanda in the United States, where it was initially approved in 2008; Ri­bomustin in some countries in the European Union (eg, Germany and Switzerland); and Levact in other countries in the European Union, including Austria, Belgium, Denmark, Finland, France, Ireland, Italy, Luxembourg, Norway, Poland, Spain, and the United Kingdom, where it was approved in 2010.2-5

The approved indications for bendamustine vary by geographic location. Treanda (bendamustine hydrochloride) for Injection, for IV infusion, is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL), and for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with ri­tuximab or a rituximab-containing regimen.3 Levact (bendamustine hydrochloride) is approved for the treatment of CLL in patients who cannot be treated with fludarabine combination therapy; for NHL in patients whose cancer progressed during or within 6 months of treatment with rituximab or rituximab-containing regimens; and for frontline treatment of multiple myeloma (MM) in combination with prednisone in patients older than age 65 years who are not eligible for autologous stem cell transplantation and who cannot be treated with thalidomide or bortezomib due to the presence of clinical neuropathy at diagnosis.2,5

Ribo­mustin (bendamustine hydrochloride) was approved for frontline treatment of indolent NHL as part of combination therapy; for advanced MM (Durie-Salmon stage II with progression or stage III) in combination with prednisone; and for CLL.6

The use of bendamustine in the United States for indications other than as described above for Treanda is considered to be off-label. Bendamustine is approved in the United States as monotherapy. It is approved in the Euro­pean Union, as noted, in combination with prednisone for MM.2,5 Benda­mustine has also been used in combination with other agents (Table 17-11).

Ongoing clinical investigations of bendamustine as monotherapy or in combination therapy in patients with hematologic malignancies or with solid tumors will be discussed in the fourth article in this series.

History of Bendamustine
The observation that nitrogen mustard induced tumor responses resulted in research on the use of alkylating agents to treat cancer.12 The alkylating agent bendamustine was first synthesized in 1963 in Jena, in the former German Democratic Republic (East Germany), at the Institute for Microbiology and Experimental Therapy.12 The first use of bendamustine was in 1969 to treat MM.13 Bendamustine was used primarily in East Germany in patients with CLL, NHL, Hodgkin disease, MM, and lung cancer. Benda­mustine was not studied systematically in clinical trials in patients until the 1990s, after German reunification.9,12 The development of bendamustine in the United States began in the early 2000s.1

Bendamustine was approved by the FDA for the treatment of CLL on March 20, 2008, and on October 31, 2008, for the treatment of indolent B-cell NHL in patients whose disease progressed during or within 6 months of treatment with ri­tuximab or a rituximab-containing regimen.8,12

Characterization of Bendamustine
Structure and Mechanism of Action
Bendamustine hydrochloride is a bifunctional mechlor­ethamine derivative with the chemical name 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1-methyl-, monohydrochloride, with an empirical molecular formula of C16H21Cl2N3O2 • HCl and a molecular weight of 394.7. Benda­mustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent.3 The structural formula of bendamustine is illustrated in Figure 1.

The alkylating activity of bendamustine resides in its mechlorethamine or nitrogen mustard moiety, which resembles the alkylating agents cyclophosphamide and chlorambucil. This is illustrated in Figure 2.

Bendamustine has a benzimidazole ring, unlike chlorambucil, which has a benzene ring. The benzimidazole ring resembles some purine analogs; it was included to add antimetabolite effects. Although this structure may add purine analog activity to the molecule, this has not been demonstrated.3 The exact mechanism of action of bendamustine is not known. It is active against both dividing and quiescent cells.3 The alkyl­ating activity of bendamustine resembles that of other alkylating agents in that it causes interstrand and intrastrand DNA crosslinks.3,12 The DNA damage, including DNA double-strand breaks caused by bendamustine, are repaired more slowly than those caused by other alkylating agents. Bendamustine, unlike other alkylating agents, appears to have a unique mechanism of activation of DNA damage stress responses and apoptosis (programmed cell death), and inhibition of mitotic checkpoints. For example, bendamustine causes an increase in the proportion of cells in the S phase of the cell cycle and downregulates genes involved in cell division.12

Bendamustine activates a base-excision DNA repair pathway, but unlike other alkylating agents it does not induce an alkyltransferase mechanism of DNA repair. This may result in less susceptibility to drug resistance. The regulation of apoptosis associated with bendamustine is also unlike that associated with other alkylating agents and appears to be stronger and more rapid.12 Bendamustine also appears to induce cell death by mitotic catastrophe, a necrotic mechanism, which is distinct from apoptosis. Therefore, even in malignant cells that are missing a functional apoptotic pathway, bendamustine has cytotoxic activity. Other nonapopto­tic mechanisms associated with bendamustine-induced cytotoxicity include depletion of adenosine triphosphate, which may make cells more susceptible to metabolic shutdown, and induction of reactive oxygen species stress pathways, which may also affect metabolic equilibrium.14

Pharmacology
Dosage and Administration
For patients with CLL, bendamustine is administered by IV infusion at a dose of 100 mg/m2 over 30 minutes on days 1 and 2 of a 28-day cycle for up to 6 cycles. For patients with NHL, bendamustine is administered by IV infusion at a dose of 120 mg/m2 over 60 minutes on days 1 and 2 of a 21-day cycle for up to 8 cycles.3

Pharmacokinetics
Pharmacokinetic parameters are summarized in Table 2.3,15

Absorption
The Cmax of bendamustine hydrochloride occurs at the end of infusion of a single IV dose (dose unspecified).3

Distribution
In in vitro studies, 94% to 96% of bendamustine was bound to human serum plasma proteins,3 primarily albumin. Only the free form is pharmacologically active.12 This binding was independent of concentration over a range of 1 to 50 µg/mL of bendamustine. There is no evidence that bendamustine displaces or is displaced by highly protein-bound drugs. Bendamustine distributes freely in human red blood cells based on concentration ratios of blood to plasma of 0.84 to 0.86 for bendamustine concentrations of 10 to 100 µg/mL.3 The role of active transport systems that might affect bendamustine distribution has not been completely evaluated. That P-glycoprotein, the breast cancer resistance protein, and/or other efflux transporters may play a role in bendamustine transport has been suggested by in vitro studies.3

Metabolism
In vitro studies show that bendamustine is primarily metabolized via hydrolysis to metabolites with low cytotoxic activity. Two active minor metabolites, M3 (gamma-hydroxy bendamustine) and M4 (N-desmethyl-bendamustine), are formed via the cytochrome P450 enzyme CYP1A2.3 M3 is present in plasma at 1/10 the concentration of bendamustine. M4 is present in plasma at 1/100 the concentration of bendamustine.3 The cytotoxic activity of bendamustine resides primarily in the original, unmetabolized compound.12 Bendamustine does not inhibit cytochrome P450 enzymes CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5 in human liver microsomes in vitro. Bendamustine did not induce metabolism of the cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 in primary human hepatocyte cultures.3 Inhibitors of CYP1A2 could potentially increase plasma concentrations of bendamustine and decrease plasma concentrations of its active metabolites. CYP1A2 inducers could potentially decrease plasma concentrations of bendamustine and increase plasma concentrations of its metabolites.3

Elimination
In preclinical studies, about 90% of radiolabeled bendamustine is recovered primarily in the feces,3 and to a lesser extent in the urine. Nonmetabolized particles make up nearly half of the bendamustine that is excreted in urine.12 Clearance of bendamustine and half-life of bendamustine and minor metabolites M3 and M4 in clinical studies are summarized in Table 2. When bendamustine is administered on days 1 and 2 of a 28-day cycle, little or no accumulation is expected.3

Renal Impairment
There have been no formal studies of the effect of renal impairment on the pharmacokinetics of bendamustine.3 In a population pharmacokinetic analysis of 31 patients receiving bendamustine at a dose of 120 mg/m2, there was no meaningful effect of renal impairment defined as a creatinine clearance (CrCl) of 40 to 80 mL/minute on the pharmacokinetics of bendamustine. Bendamustine has not been studied in patients with a CrCl of less than 40 mL/minute. Because of these limited data, bendamustine should be used with caution in patients with mild or moderate renal impairment, and should not be used in patients with a CrCl of less than 40 mL/minute.3

Hepatic Impairment
There have been no formal studies of the effect of hepatic impairment on the pharmacokinetics of bendamustine.3 In a population pharmacokinetic analysis of 26 patients receiving bendamustine at a dose of 120 mg/m2, there was no meaningful effect of mild hepatic impairment on the pharmacokinetics of bendamustine. In this study, mild hepatic impairment was defined as total bilirubin no greater than the upper limit of normal (ULN), aspartate aminotransferase (AST) ?ULN to 2.5 times the ULN, and/or alkaline phosphatase (ALP) ?ULN to 5.0 times the ULN. Bendamustine has not been studied in patients with moderate or severe hepatic impairment. Because of these limited data, bendamustine should be used with caution in patients with mild hepatic impairment. Bendamustine should not be used in patients with moderate hepatic impairment, defined as AST or ALT 2.5 to 10 times the ULN and total bilirubin 1.5 to 3 times the ULN, or in patients with severe hepatic impairment, defined as total bilirubin greater than 3 times the ULN.3

Pharmacodynamics
Age
The pharmacokinetics of bendamustine were similar in patients younger than and at least age 65 years in a study of adults aged 31 through 84 years.3 In studies in patients with CLL and NHL, there were no clinically significant differences in the safety profile of bendamustine in patients who were at least aged 65 years compared with younger patients.3

Bendamustine has been studied in a single phase 1/2 trial in pediatric patients aged 1 to 19 years with acute lymphocytic leukemia (n=27) or acute myeloid leukemia (n=16). The exposures as measured by AUC (area under the concentration time curve from 0 to 24 hours) and Cmax were similar to those measured in adults at the same dose (120 mg/m2 IV administered over 60 minutes). Note that the efficacy of bendamustine has not been established in pediatric patients.3

Gender
There were no differences in the pharmacokinetics of bendamustine in male and female patients3 and no differences in safety between male and female patients in studies of patients with either CLL or NHL.3

Race
The effect of race on safety and/or efficacy of bendamustine has not been determined. Although a small number (n=6) of Japanese subjects had an average exposure that was 40% higher than that of non-Japanese subjects (number not specified) receiving the same dose, the significance of this difference is not known.3

Adverse Events
In adult patients with NHL, there was a correlation between nausea and the Cmax of bendamustine.3

Part 2 in the Series
The next article in this series will present the efficacy data for the registration studies of bendamustine in patients with CLL and NHL.

References

  1. Cheson BD. Introduction to bendamustine. Clin Adv Hem Onc. 2011; 9(suppl 19):2.
  2. Medical News Today. New anti-cancer drug, Levact® (bendamustine), approved in the UK for low grade non-Hodgkin’s lymphoma. http://www.medicalnewstoday.com/releases/201049.php. September 15, 2010.
  3. Treanda [prescribing information]. Cephalon, Inc: Frazer, PA; Revised 8/2012.
  4. Bendamustine (Ribomustin®/Treanda®/Levact®) for indolent non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia and multiple myeloma. Horizon Scanning in Oncology. Ludwig Boltzmann Institute. July 7, 2010.
  5. European Medicines Agency. Questions and answers on Levact and associated names (bendamustine hydrochloride, 2.5 mg/ml, powder for concentrate for solution for infusion). www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Levact_29/WC500075906.pdf. July 7, 2010.
  6. Mundipharma Oncology. Ribomustin® Bendamustin. The hybrid alkyl­ating agent. EC Safety Data Sheet. www.chemblink.com/MSDS/MSDSFiles/3543-75-7_Mundipharma.pdf. March 2007.
  7. Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:3383-3389.
  8. Abou-Nassar K, Brown JR. Novel agents for the treatment of chronic lymphocytic leukemia. Clin Adv Hem Onc. 2010;8:886-895.
  9. Aldoss IT, Blumel SM, Bierman PJ. The role of bendamustine in the treatment of indolent non-Hodgkin lymphoma. Cancer Manag Res. 2009;1:155-165.
  10. Cheson BD, Wendtner CM, Pieper A, et al. Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: treatment recommendations from an international consensus panel. Clin Lymphoma Myeloma Leuk. 2010;10:21-27.
  11. Lu K, Wang X. Therapeutic advancement of chronic lymphocytic leukemia. J Hematol Oncol. 2012;5:55.
  12. Tageja N, Nagi J. Bendamustine: something old, something new. Cancer Chemother Pharmacol. 2010;66:413-423.
  13. Apostolopoulos C, Castellanl L, Stebbing J, et al. Bendamustine as a model for the activity of alkylating agents. Future Oncol. 2008;4:323-332.
  14. Leoni L. The alkylating properties of bendamustine. Clin Adv Hem Onc. 2011;9(suppl 19):3-5.
  15. Levact® bendamustine HCl. Product Monograph. Napp Pharmaceu­ticals Limited. June 2010.
Uncategorized - January 9, 2013

Stakeholder’s Perspective: Pharmacy Considerations

Since the approval of bendamustine, healthcare practitioners have additional treatment options available to patients with specific hematologic malignancies. In the United States, bendamustine was approved for patients with chronic lymphocytic leukemia (CLL) or indolent B-cell non-Hodgkin lymphoma (NHL) who had progressed within 6 months of receiving rituximab-containing regimens. In Europe, [ Read More ]

Uncategorized - January 9, 2013

Stakeholder’s Perspective: Physician Considerations

Bendamustine has an interesting history that spans more than 50 years. Bendamustine was first synthesized in the early 1960s in the former East Germany. It was first used to treat multiple myeloma and was subsequently extended to patients with chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma. Unfortunate­ly, [ Read More ]