Ribomustin Mechanism of Action

Pharmacotherapeutic Group: Antineoplastic agents, alkylating agents. ATC Code: L01AA09.
Pharmacology: Pharmacodynamics: Bendamustine is an alkylating antitumor agent with unique activity containing a purine-like benzimidazole ring. 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. Bendamustine is active against both quiescent and dividing cells.
The exact mechanism of action of bendamustine remains unknown.
The antitumor effect of bendamustine hydrochloride has been demonstrated by several in- vitro studies in different human tumor cell lines (breast cancer, non-small cell and small cell lung cancer, ovary carcinoma and different leukemia) and in- vivo in different experimental tumor models with tumors of mouse, rat and human origin (melanoma, breast cancer, sarcoma, lymphoma, leukemia and small cell lung cancer).
Bendamustine hydrochloride showed an activity profile in human tumor cell lines different to that of other alkylating agents. The active substance revealed no or very low cross-resistance in human tumor 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.
Chronic lymphocytic leukemia: The indication for use in chronic lymphocytic leukemia is supported by a single open label study comparing bendamustine with chlorambucil. In the prospective, multicenter, randomized study, 319 previously untreated patients with chronic lymphocytic leukemia stage Binet B or C requiring therapy were included. The first line therapy with bendamustine hydrochloride 100 mg/m² i.v. on days 1 and 2 (BEN) was compared to treatment with chlorambucil 0.8 mg/kg days 1 and 15 (CLB) for 6 cycles in both arms. Patients received allopurinol in order to prevent tumor lysis syndrome.
Patients with BEN have a significantly longer median progression-free survival than patients with CLB treatment (21.5 versus 8.3 months, p < 0.0001 in the latest follow-up). Overall survival was not statistically significantly different (median not reached). The median duration of remission is 19 months with BEN and 6 months with CLB treatment (p < 0.0001). The safety evaluation in both treatment arms did not reveal any unexpected adverse reactions in nature and frequency. The dose of BEN was reduced in 34% of the patients. Treatment with BEN was discontinued in 3.9% of patients due to allergic reactions.
Indolent non-Hodgkin's lymphomas: The indication for indolent non-Hodgkin's lymphomas relied on two uncontrolled phase II trials.
In the pivotal prospective, multi-center, open study 100 patients with indolent B-cell non- Hodgkin's lymphomas refractory to rituximab mono- or combination therapy were treated with BEN single agent. Patients received a median of 3 previous chemotherapy or biologic therapy courses. The median number of previous rituximab-containing courses was 2. The patients had no response or progress within 6 months after rituximab treatment. The dose of BEN was 120 mg/m² i.v. on days 1 and 2 planned for at least 6 cycles. Duration of treatment depended on response (6 cycles planned). The overall response rate was 75% including 17% complete (CR and CRu) and 58% partial response as assessed by independent review committee. The median duration of remission was 40 weeks. BEN was generally well tolerated when given in this dose and schedule.
The indication is further supported by another prospective, multicenter, open study including 77 patients. The patient population was more heterogeneous including: indolent or transformed B- cell non-Hodgkin's lymphomas refractory to rituximab mono- or combination therapy. The patients had no response or progress within 6 months or had an untoward reaction to prior rituximab treatment. Patients received a median of 3 previous chemotherapy or biological therapy courses. The median number of previous rituximab-containing courses was 2. The overall response rate was 76% with a median duration of response of 5 months (29 [95% CI 22.1, 43.1] weeks).
Pharmacokinetics: Distribution: The elimination half-life t_½β 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).
Metabolism: 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 1A2, CYP 2C9/10, CYP 2D6, CYP 2E1 and 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 > oxidized metabolite > N-desmethyl bendamustine. In the bile, primarily polar metabolites are eliminated.
Hepatic impairment: In patients with 30 - 70% tumor infestation of the liver and mild hepatic impairment (serum bilirubin < 1.2 mg/dL) the pharmacokinetic behavior 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_½β, 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_½β, volume of distribution and clearance.
Elderly subjects: Subjects up to 84 years of age were included in pharmacokinetic studies. Higher age does not influence the pharmacokinetics of bendamustine.
Toxicology: Non-Clinical Information: Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: Histological investigations in dogs showed macroscopic visible hyperemia of the mucosa and hemorrhagia in the gastrointestinal tract. Microscopic investigations showed extensive changes of the lymphatic tissue indicating an immunosuppression and tubular changes of kidneys and testis, as well as atrophic, necrotic changes of the prostate epithelium.
Animal studies showed that bendamustine is embryotoxic and teratogenic.
Bendamustine induces aberrations of the chromosomes and is mutagenic in-vivo as well as in- vitro. In long-term studies in female mice bendamustine is carcinogenic.