Characterization of two phase I metabolites of bendamustine in human liver microsomes and in cancer patients treated with bendamustine hydrochloride

Teichert, Jens; Baumann, Frank; Qi, Chao; Franklin, Craig L.; Bailey, Brandy; Hennig, Lothar; Caca, Karel; Schoppmeyer, Konrad; Patzak, Ulrich; Preiss, R

doi:10.1007/s00280-006-0331-5

Cited by 65 publications

(71 citation statements)

References 13 publications

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“…Hence, we calculated an amount excreted in urine of 5.2 and 1.6% for g-OH-BM and N-dimethyl-BM, respectively, expressed as the sum of all compounds quantified in this study. These figures are in agreement with results observed in a previous P k study (Teichert et al, 2006).…”

Section: Discussionsupporting

confidence: 83%

“…The elimination of unchanged BM and these metabolites is primarily renal (Weber et al, 1991;Preiss et al, 1998;Teichert et al, 2003). However, the main biotransformation products N-dimethyl-BM and g-OH-BM are excreted with the bile (Bezek et al, 1991;Preiss et al, 1998;Teichert et al, 2006). In preclinical studies, acute toxicity is observed in bone marrow and intestines, while the kidneys, testes, prostate, and the lymphatic tissues are prone to subacute toxicity (Horn et al, 1985).…”

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confidence: 99%

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A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours

et al. 2007

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The aim of the study was to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), and the pharmacokinetic profile (P k ) of bendamustine (BM) on a day 1 and 2 every 3 weeks schedule and to recommend a safe phase II dose for further testing. Patients with solid tumours beyond standard therapy were eligible. A 30-min intravenous infusion of BM was administered d1 þ d2 q 3 weeks. The starting dose was 120 mg m À2 per day and dose increments of 20 mg m À2 were used. Plasma and urine samples were analysed using validated high-performance liquid chromatography/fluorescence assays. Fifteen patients were enrolled. They received a median of two cycles (range 1 -8). The MTD was reached at the fourth dose level. Thrombocytopaenia (grade 4) was dose limiting in two of three patients at 180 mg m À2 . One patient also experienced febrile neutropaenia. Lymphocytopaenia (grade 4) was present in every patient. Nonhaematologic toxicity including cardiac toxicity was not dose limiting with this schedule. Mean plasma P k values of BM were t max 35 min, t 1/2 49.1 min, V d 18.3 l m À2 , and clearance 265 ml min À1 m À2 . The mean total amount of BM and its metabolites recovered in the first micturition was 8.3% (range 2.7 -26%). The MTD of BM in the present dose schedule was 180 mg m À2 on day 1 þ 2. Thrombocytopaenia was dose limiting. The recommended dose for future phase II trials with this schedule is 160 mg m À2 per day.

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Section: Discussionsupporting

confidence: 83%

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confidence: 99%

A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours

et al. 2007

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“…Nonmetabolized particles have been found to constitute 45% of the excreted portion of the drug in urine. 33 Following a 60-minute intravenous administration in patients with NHL, serum bendamustine declined in a rapid biphasic manner (t½α = 17 minutes, t½β = 42 minutes) and a slow terminal phase (t½c = 110 hours), but the terminal phase composed less than 1% of the total AUC, and therefore, the half-life of the β-phase represents bendamustine mean half-life, which is approximately 40 minutes. 34 The drug is eliminated mainly via feces and to a lesser extent in the urine.…”

Section: Dovepressmentioning

confidence: 99%

“…28,29 At steady state, bendamustine has a volume of distribution (V d ) of 20 to 25 L. [28][29][30][31][32] Bendamustine metabolism predominantly occurs through hydrolysis, and phase I metabolite formation seems to be mediated via hepatic cytochrome P450 1A2. 33 Hydrolysis generates active and inactive metabolites. Nevertheless, active metabolites such as gamma-hydroxy-bendamustine (M3) and N-desmethyl-bendamustine (M4) occur in negligible concentrations compared to the parent component, and this verified that the cytotoxic activity of bendamustine is mainly generated by the original compound.…”

Section: Dovepressmentioning

confidence: 99%

The role of bendamustine in the treatment of indolent non-Hodgkin lymphoma

Aldoss¹,

Blumel²,

Bierman³

2009

CMAR

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Abstract:There is no consensus on recommendations for the treatment of relapsed and refractory indolent non-Hodgkin lymphoma (NHL). Bendamustine hydrochloride (bendamustine) has recently been approved for treatment of these patients. Bendamustine is a uniquely structured alkylating agent that lacks cross-resistance with other alkylators. This agent has a high degree of activity against a variety of tumor cell lines. Clinically, bendamustine has demonstrated activity against indolent NHL, chronic lymphocytic lymphoma, multiple myeloma and mantle cell lymphoma. Moreover, studies have validated its activity in patients with indolent NHL who are resistant to purine analogs and rituximab. The cytotoxic activity of bendamustine has been shown to be synergistic with rituximab in hematological malignancies. The incidence of alopecia is significantly less than with other alkylating agents. Myelosuppression is the major toxicity associated with bendamustine.

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“…Bendamustine undergoes extensive first-pass metabolism via CYP1A2-catalyzed N-dealkylation and gamma hydroxylation. 13 The resulting metabolites include gamma-hydroxy-bendamustine (M3), which retains an activity level similar to the parent compound and the relatively inactive N-desmethyl-bendamustine (M4). Phase II metabolism consists of conjugation with gluthathione and may also play a role in the elimination of bendamustine as demonstrated in cholangiocarcinoma.…”

Section: Pharmacologymentioning

confidence: 99%

The expanding role of bendamustine in chronic lymphocytic leukemia

Nair¹,

Ujjani²

2015

BLCTT

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Abstract:As the most prevalent form of adult leukemia, chronic lymphocytic leukemia (CLL) affects thousands of patients each year. Given the indolent nature of the disease, symptomatic patients frequently experience multiple relapses throughout their clinical course. Better therapeutic options are needed, particularly for the elderly population that characterizes the majority of affected patients. Bendamustine, a hybrid alkylating agent, has demonstrated remarkable activity in CLL in conjunction with a tolerable safety profile. Although historically used in relapsed and refractory disease, it has recently gained a role in the front-line setting, including younger, physically fit patients. Current investigatory efforts are focused on exploring the combination of bendamustine with novel therapies in CLL.

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Characterization of two phase I metabolites of bendamustine in human liver microsomes and in cancer patients treated with bendamustine hydrochloride

Cited by 65 publications

References 13 publications

A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours

A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours

The role of bendamustine in the treatment of indolent non-Hodgkin lymphoma

The expanding role of bendamustine in chronic lymphocytic leukemia

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