Bendamustine hydrochloride

Product description

Bendamustine hydrochloride was first successfully developed in the early 1860s by the Ozegowski and his colleagues in the “Microbiology Experiment Association (Jena in Germany)”. The original purpose of developing it is intended to make a kind of alkylated chloremethine (a non-effective alkylating agent) be connected to a purine and amino acids. Compared with the chlorambucil, the main advantage of the newly synthesized compound is its water solubility. It was then widely applied. However, it is not until the end of the Cold War before the drug had been applied in Europe to clinical studies in either a number of single medication or in combination with other drugs for treating various kinds of blood malignancies and non-Hodgkin's lymphoma, multiple myeloma, CLL and breast cancer and some other solid tumors. The efficacy is very impressive. The drug had significantly reduced the recurrence rate and death rate with small adverse reactions and good security. So far, the clinical protocols of both monotherapy and combination therapy of bendamustine hydrochloride has been designated as either first-or second-line treatment option for treating various kinds of hematological malignancies by Europe and America clinical guidelines.
From 1971 to 1992, Bendamustine was sold by the Jena pharmaceutical companies in the trade name of “Cytostasan”. From 1993, the cell growth inhibitor entered into market with the trade name “Ribomustine” mediated by Ribosepharm Company.
In 2003, the bendamustine hydrochloride product developed by German Ribosepharm Company entered into market in Germany with the trade name "Ribomustin".
In 2008, the Bendamustine hydrochloride injection product developed by the United States Cephalon Company entered into market in United States under the trade name “Treanda” which is used for the treatment of the relapsed and refractory B-cell non-Hodgkin’s lymphoma which is failed be to be treated rituximab monotherapy.

Indications

In March 2008, the US Food and Drug Authority (briefly called FDA) first approved bendamustine hydrochloride for the treatment of chronic lymphocytic leukemia (CLL). In October of the same year, FDA had approved for the second indication of the drug: the indolent B-cell non-Hodgkin's lymphoma (NHL) patients who have their symptoms still be in progress during the treatment with either rituximab or rituximab-containing regimen or within 6 months of the treatment.

The dose and medication

The lyophilized powder of bendamustine is white to off-white. Its specification is 100mg/tube. This storage temperature of this medicine should not exceed 30 ℃ and should be protected from light and should be temporarily prepared before use.
Preparation process: Every 100 mg of the drug must be first dissolved in 20ml of sterile water (for injection), fully shake until completely dissolve it into a clear, colorless or pale yellow solution with dissolution time generally being not more than 5 minutes and the final dissolving concentration being 5mg/ml. Within 30 minutes after the dissolution, extract certain amount of bendamustine solution according to the necessity, transfer it to a 500ml Sodium Chloride Injection (0.9%) or glucose-sodium chloride injection (2.5%/0.45%), and make sure the final concentration of benzene bendamustine in injection be between 0.2~0.6mg/ml. The prepared injection can be kept refrigerated for 24 hours at 2~8 ℃, or stored for 3 hours at room temperature and natural light.
Upon the treatment of chronic lymphocytic leukemia, take 28-day as one treatment cycle. It normally takes six treatment cycles. Drugs should be administered at the first day and the second day of each cycle of treatment; the recommended dose is 100mg/m2. The drug is administered through intravenous infusion with each administration time being no less than 30 minutes.
Upon treatment of indolent B-cell non-Hodgkin's lymphoma, take 21-day as one treatment cycle. It normally takes eight treatment cycles. The drugs should be administered at the first day and the second day of each cycle of treatment with the recommended dose being 120 mg/m2 and each administration time being no less than 60 minutes.

Pharmacological effects

The exact mechanism of action of bendamustine hydrochloride is not yet clear. But it is already known that the drug is a carry a chloremethine derivative carrying a purine-like benzimidazole ring with dual mechanisms of action of both alkylating agents and purine analogs (anti-metabolite). Bendamustine hydrochloride can cause cell death through several different pathways and is effective in treating both division cells as well as stationary phase cells.
The above information is edited by the chemicalbook of Dai Xiongfeng.

Pharmacokinetics

The plasma protein binding rate of bendamustine hydrochloride should be 94% to 96%. Data has shown that this drug is generally not mutually substitutable with other protein bound drugs. The mean steady-state volume of distribution of bendamustine hydrochloride is approximately 25L. Its whole blood/plasma concentration ratio is 0.84 to 0.86. Bendamustine hydrochloride is mainly metabolized through hydrolysis while forming low-cytotoxic metabolites. The drug can be converted to two active metabolites, M3 and M4 via CYP1A2 metabolic pathway. But the plasma concentrations of both the two metabolites only correspond to 1/10 and 1/100, respectively of the parent compound, and therefore, it can be speculated that the cytotoxic effect of bendamustine mainly orginiates from itself instead of its metabolites.

Contraindications

Patients who are allergic to Bendamustine hydrochloride and mannitol should be disabled for using it.

Drug Interactions

When used in combination with the CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin), it may increase blood concentrations of bendamustine while causing the decrease of the concentration of its metabolites M3 and M4.
When used in combination with CYP1A2 inducers (such as omeprazole, smoking, etc.), it may reduce the blood concentration of bendamustine while increasing the concentration of it metabolites M3 and M4.

Adverse reactions and side effects

Common adverse reactions include nausea, vomiting, diarrhea, fatigue, weakness, skin rashes, itching, some kinds of infection symptoms and body signs (such as persistent sore throat, fever and chills), easy for bruising/bleeding and ulcers in the mouth; in some serious adverse reactions, there may be bone marrow suppression and tumor lysis syndrome.
It may cause mild or severe allergic reaction. During the process of administration or the early phase of post-administration, there may be some allergic symptoms such as rash, facial swelling, and difficulty in breathing.
It may negatively affect the fetus, so women who are during treatment and within three months after treatment should take appropriate contraceptive measures as well as stop breast-feeding.

Description

Bendamustine is a purine analog and DNA alkylating agent. It inhibits growth of SKW-3, Reh, CML-T1, BV-173, and HL-60 leukemia cell lines (IC₅₀s = 27.0, 28.6, 15.6, 20.8, and 57.7 μM, respectively) but not MCF-7 and MDA-MB-231 breast cancer cell lines (IC₅₀s = >200 and >200 μM, respectively). It kills B cell-chronic lymphocytic leukemia (B-CLL) cells derived from naïve and bendamustine-pretreated patients (LD₅₀s = 6.8-8.3 and 3.8-4.9 mg/ml, respectively). Bendamustine (50 mg/kg) inhibits tumor growth by 9% and 96% alone and in combination with ofatumumab, respectively, in a JVM-3 CLL mouse xenograft model. It activates the DNA-damage stress response, the base excision DNA repair pathway, and apoptosis, as well as inhibits mitotic checkpoints and induces mitotic catastrophe. Formulations containing bendamustine have been used to treat CLL and non-Hodgkin lymphoma.

Chemical Properties

Pale Brown Crystals

Uses

Used as an anticancer drug

Uses

Bendamustine HCL is a DNA-damaging agent with IC50 of 50 μM.

Uses

alkylating agent recently approved by the FDA for treatment of Chronic Lymphocytic Leukemia

Uses

Bendamustine hydrochloride hydrate has been used as:

• a chemotherapy agent for chronic lymphocytic leukemia (CLL) samples to monitor spliced and unspliced gene expression
• an inhibitor to E3 ubiquitin-protein ligase RNF3 (HOIP) inmatrix-assisted laser desorption ionization time-of-flight mass spectrometry(MALDI-TOF) assay
• a cytotoxic chemotherapeutic drug in high-throughput screening to test interaction with BAY87-2243

brand name

Ribomustine (Amcis AG, Switzerland).

General Description

Bendamustine comprises 2-chloroethylamine alkylating group, a butyric acid side chain and a benzimidazole ring in its structure and is a nitrogen mustard. It is catabolized in the liver by the enzyme cytochrome P450 1A2 into γ hydroxyl-bendamustine and N-desmethyl-bendamustine.

Biological Activity

Cytostatic agent that displays activity in non-Hodgkin's lymphomas. Exhibits bifunctionality; combines DNA alkylating properties with those of purine analogs.

Biochem/physiol Actions

Bendamustine is a therapeutic agent employed in treating lymphomas and chronic lymphocytic leukemia. It may be useful in central nervous system (CNS) malignancies treatment regimen due to its penetration capacity into brain tissue. Bendamustine is a promising candidate for non-Hodgkin lymphoma and Hodgkin lymphoma therapies.

Clinical Use

Alkylating agent:

CLL, NHL and multiple myeloma

Synthesis

3543-74-6

3543-75-7

Example 9 Synthesis of 4-[5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoic acid (9, bendamustine hydrochloride hydrate) 1. 250 g (0.7154 mol) of ethyl 5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzimidazole-2-butanoate (compound 7) was dissolved in 2000 ml of dichloromethane and cooled to -1 °C. 212 g (1.78 mol) of thionyl chloride was slowly added dropwise over 30 min, controlling the reaction temperature to not exceed -1 °C. After the dropwise addition was completed, the reaction mixture was continued to be stirred at -1 °C for 30 min, then gradually warmed up to room temperature and stirred for 16 hours. 2. The solvent and excess thionyl chloride were removed by vacuum distillation to afford the hydrochloride salt of compound 8. To the residue, 2.6 kg of 37% hydrochloric acid and 1.4 L of water were added, heated to 75 °C and kept for 30-40 minutes for the hydrolysis reaction of the ester. Subsequently, 25 g of activated carbon was added and stirred at 75°C for 10 minutes, filtered and the filtrate was concentrated in vacuum. 3. The concentrated residue was dissolved in 1000 ml of water, heated to 55 °C and then cooled to 50 °C, then further cooled to -2 °C and kept for 30 min to promote crystallization. The crude product (9) was collected by filtration, washed sequentially with 250 g of water and 200 g of acetone, and dried under vacuum at 35 °C for 2 h. 245 g (0.5936 mol, 83% yield) of the crude product was obtained, with a water content of 4.5%. 4. 245 g of the crude product (9) was dissolved in 330 g of 37% hydrochloric acid, 1.28 kg of water (ca. 35 °C) and 650 g of acetone (ca. 35 °C) were added and stirred for 10 min. 0.5g of bendamustine hydrochloride hydrate was added as a crystalline seed, and the mixture was cooled to -20°C over a period of 2 hours and held at this temperature for 90 minutes. The precipitate was filtered and washed first with a mixture of 120 g of water and 90 g of acetone and then with 275 g of acetone. 5. The purified bendamustine hydrochloride hydrate was dried under vacuum at 35°C for about 2 hours to give 225 g (0.545 mol, 76.2% yield) of pure product (>99.8% content). The water content can be adjusted to about 1% by vacuum drying at 50°C (theoretical water content of 4.4% for the single hydrate).

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).

Metabolism

A major route of clearance of bendamustine is the hydrolysis to monohydroxy- and dihydroxybendamustine. 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. Excreted in the urine and faeces as unchanged drug and metabolites.

storage

Desiccate at RT

References

[1]. leoni lm, bailey b, reifert j, bendall hh, zeller rw, corbeil j, elliott g, niemeyer cc. bendamustine (treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. clin cancer res. 2008 jan 1;14(1):309-17.
[2]. gaul l, mandl-weber s, baumann p, emmerich b, schmidmaier r. bendamustine induces g2 cell cycle arrest and apoptosis in myeloma cells: the role of atm-chk2-cdc25a and atm-p53-p21-pathways. j cancer res clin oncol. 2008 feb;134(2):245-53.
[3]. roué g, lópez-guerra m, milpied p, pérez-galán p, villamor n, montserrat e, campo e, colomer d. bendamustine is effective in p53-deficient b-cell neoplasms and requires oxidative stress and caspase-independent signaling. clin cancer res. 2008 nov 1;14(21):6907-15.
[4]. cai b, wang s, huang j, lee ck, gao c, liu b. cladribine and bendamustine exhibit inhibitory activity in dexamethasone-sensitive and -resistant multiple myeloma cells. am j transl res. 2013;5(1):36-46.