Bendamustine

Bendamustine is a mechlorethamine derivative synthesised by Ozegowski and Krebs from the former East Germany in 1963. The  molecule has three parts,

  1. The alkylator mechloethamine,
  2. Benzimidazole ring that mimics purines
  3. Butyric acid side chain.

Each of these part has potential anti-malignacy action but only the alkylating actions are of clinical significance.

Mechanism of Action

Bendamustine acts as a classical chlorethyl alkylating agent. It causes inter and intrastrand DNA cross links that result in DNA strand breaks. The number of DNA strand breaks caused by bendamustine is grater than those caused by cyclophosphamide or melphalan. In addition the breaks are repaired slowly. This is probably because of the bulky structure of bendamustine. It has a partial cross sensitivity against other alkylating agents.

The benzimidazole side chain mimics purines and butyric acid side chain can react with membranes and proteins.  These actions do not contribute to the anti-tumour effect of bendamustine.

Mechanisms of Resistance

Resistance to bendaustime may develop because  of

Increased activity of DNA repair enzymes

Increased expression of sulfhydryl proteins, e.g. glutathione and glutathione-related enzymes

Bendamustine is partially cross-resistance with other alkylators.

Pharmacokinetics

  1. Absorption and Distribution: Bendamustine has a high oral bioavailability of 90% but no oral preparation is available. It is tightly (94%-96%) bound to human serum plasma proteins. Protein binding is not affected by hypoalbuminaemia.  It does not appear to displace other drugs or be displaced by other drugs. It is mainly distributed in the extracellular space and has a steady state volume of distribution of 25 L.
  2. Elimination: It is metabolised by hydrolysis. Active metabolites are formed as a result of drugs metabolism but theses have little clinical significance.  The half-life after a 30 minute infusion is 40 minutes with clearance of 700ml/min.
  3. Effect of Renal Impairment: Renal impairment with creatinine clearance unto 40 ml/min does not affect the elimination of bendamiustine. The effect of more severe renal failure is not studied.
  4. Effect of Hepatic Impairment: Mild Hepatic impairment does not have an effect on bendamustine elimination. The effect of moderate and severe liver impairment is unknown.

Toxicity

  1. Myelosupression: The main toxicity is myelosupression with about half the patients having grade 3 or 4 neutropenia. The incidence of febrile neutropenia is about 7%. Grade 3  to 4 thromboctopenia is about 24%. Anaemia is less common.
  2. Nausea and vomiting is usually mild to moderate
  3. Infusion reactions: infusion reaction is characterised by fevers, hypotension, back and muscle pain, chills, and rigours and may be seen within the 24 hours of infusion. It may be seen unto the third cycle. Steroids may help in patients getting infection reactions.
  4. Skin Toxicity: Skin rash and bullous exanthema
  5. Tumour lysis syndrome
  6. Carcinogenicity: Bendamustine has been associated with myelodysplastic syndrome and acute leukaemia.

Indications

  1. Chronic Lymphocytic leukaemia
  2. Low grade non-Hodgkin lymphoma
  3. Other disease wherebendamustine is used but the role is not established:
    1. Multiple Myeloma
    2. Acute Leukaemia
    3. Solid Tumours – breast cancer, small cell lung cancer, germ cell tumour

Dose

  1. Chronic Lymphocytic leukaemia:
    1. Single Agent: 100mg/m2 day 1 and 2 every 4 weeks
    2. With rituximab: 90mg/m2 day 1 and 2 when used with rituximab
  2. Non-Hodgkin Lymphoma:
    1. Single Agent: 120mg/m2 day 1 day 2 of a 21 day cycle.
    2. With Rituximab:  90mg/m2 o day 1 and day 2 of a 28 day cycle

Dosing in Special Populations

  1. Pregnancy:  Bendamustine is mutagenic.
  2. Paediatric Patients: Safety of bendamustine in paediatric population is not established
  3. Renal Failure: Bendamustine should not be used in patients with creatine clearance of less than 40ml/min
  4. Hepatic failure: Bendamustine should not be used in patients with moderate or severe hepatic impairment (bilirubin >3 X upper limit of normal or bilirubin 1.5-3 X upper limit of normal with AST or ALT 2.5-10X normal)

 

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