Bendamustine Kabi Mechanism of Action

Pharmacotherapeutic group: Antineoplastic agents, alkylating agents. ATC code: L01AA09.
PHARMACOLOGY: Pharmacodynamics: Bendamustine is an alkylating antitumour agent with unique activity. The antineoplastic and cytocidal effect of bendamustine is based essentially on a cross-linking of DNA single and double strands by alkylation. As a result, DNA matrix functions and DNA synthesis and repair are impaired. The antitumour effect of bendamustine has been demonstrated by several in-vitro studies in different human tumour cell lines (breast cancer, non-small cell and small cell lung cancer, ovarian carcinoma and different leukaemia) and in-vivo in different experimental tumour models with tumours of mouse, rat and human origin (melanoma, breast cancer, sarcoma, lymphoma, leukaemia and small cell lung cancer).
Bendamustine showed an activity profile in human tumour cell lines different to that of other alkylating agents. The active substance revealed no or very low cross-resistance in human tumour cell lines with different resistance mechanisms at least in part due to a comparatively persistent DNA interaction. Additionally, it was shown in clinical studies that there is no complete cross-resistance of bendamustine with anthracyclines, alkylating agents or rituximab. However, the number of assessed patients is small.
Pharmacokinetics: Distribution: The elimination half-life t_½ß after 30 min i.v. infusion of 120 mg/m² area to 12 subjects was 28.2 minutes.
Following 30 min i.v. infusion the central volume of distribution was 19.3 l. Under steady-state conditions following i.v. bolus injection the volume of distribution was 15.8-20.5 l.
More than 95% of the substance is bound to plasma proteins (primarily albumin).
Biotransformation: A major route of clearance of bendamustine is the hydrolysis to monohydroxy- and dihydroxy-bendamustine. Formation of N-desmethyl-bendamustine and gamma-hydroxy-bendamustine by hepatic metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Another major route of bendamustine metabolism involves conjugation with glutathione.
In-vitro bendamustine does not inhibit CYP 1A4, CYP 2C9/10, CYP 2D6, CYP 2E1 or CYP 3A4.
Elimination: The mean total clearance after 30 min i.v. infusion of 120 mg/m² body surface area to 12 subjects was 639.4 ml/minute. About 20% of the administered dose was recovered in urine within 24 hours. Amounts excreted in urine were in the order monohydroxy-bendamustine > bendamustine > dihydroxy-bendamustine > oxidised metabolite > N-desmethyl bendamustine. In the bile, primarily polar metabolites are eliminated.
Hepatic impairment: In patients with 30 - 70% tumour infestation of the liver and mild hepatic impairment (serum bilirubin <1.2 mg/dl) the pharmacokinetic behaviour was not changed. There was no significant difference to patients with normal liver and kidney function with respect to C_max, t_max, AUC, t_½ß, volume of distribution and clearance. AUC and total body clearance of bendamustine correlate inversely with serum bilirubin.
Renal impairment: In patients with creatinine clearance > 10 ml/min including dialysis dependent patients, no significant difference to patients with normal liver and kidney function was observed with respect to C_max, t_max, AUC, t_½ß, volume of distribution and clearance.
Elder subjects: Subjects up to 84 years of age were included in pharmacokinetic studies. Higher age does not influence the pharmacokinetics of bendamustine.