Poster Presenter
Pharmacokinetics and Toxicity Profile
Of Bendamustine In Patients With Impaired Liver Function.
Preiss R. Teichert J., Athmani A., Dollinger M., Preiss S,
Schoppmeyer K., Thermann P. Zipprich A.
Germany
Bendamustine, a highly effective anti-cancer
agent against malignant lymphoproliferative disorders was developed
in Germany and has been approved in Germany as RibomustinT for the
treatment of chronic lymphocytic leukaemia (CLL), as first-line
combination therapy of advanced indolent non-Hodgkin's lymphomas
(NHL), and for the treatment of advanced multiple myeloma. In 2008,
bendamustine received US FDA as TreandaT for the initial therapy
of CLL and the treatment of indolent B-cell NHL that has progressed
during or within six months of treatment with a regimen that included
rituximab. There are numerous clinical trials currently under way
to optimize the combination therapy and the treatment benefit mainly
for patients with lymphoproliferative disorders.
Bendamustine, primarily a bifunctional alkylating agent, provides
a unique cytotoxic mechanism hypothetically due to an additional
purine antimetabolite mechanism of action. Bendamustine undergoes
extensive hepatic metabolism and elimination. To date, we identified
16 different phase I metabolites and conjugates considerably contributing
to biliary excretion of bendamustine in tumour patients (1, 2).
There is no formal study to assess the effect of liver impairment
on the pharmacokinetics and toxicity of bendamustine in cancer patients
and dosing recommendation as well in the scientific literature up
to now.
In a phase II study evaluating the clinical activity of bendamustine
in 13 Child-Pugh A and B class patients (11 m/2 f) with advanced
hepatocellular carcinoma (HCC) and disturbed liver function, some
of them pre-treated with sorafenib, the pharmacokinetics of B and
its metabolites and the bendamustine related toxicity have been
investigated. In HCC patients, CT and MRI technique revealed moderate
or strong tumour involvement of the liver and the mean levels of
GGT and SGOT were elevated 10-fold and those of bilirubin 2.5-fold
compared to the reference group. Reference group included 12 patients
(5 m/7 f) with various tumour types of non-hepatic origin resistant
to all other therapies. All the subjects in both groups had normal
renal function. Bendamustine HCl 120 mg/m2 was given intravenously,
daily for 2 consecutive days. Plasma concentrations of bendamustine
and its metabolites were determined using a validated HPLC assay
with fluorescence detection. Toxicity was scored over 4 weeks according
to NIH/NCI criteria. B clearance tended to decrease in HCC (mean
values: 304 vs. 639 ml/min, non-significantly). Mean terminal half-life
of B was significantly prolonged in subjects with hepatic impairment
(47 vs. 33 min. p < 0.01). Subjects with HCC had significantly
lower (p < 0.05) plasma concentrations of gamma-hydroxy-bendamustine
(equi-effective with bendamustine) and showed a trend towards decreased
plasma concentrations of N-desmethyl-bendamustine (10-fold less
active than bendamustine) compared to the reference group. However,
the plasma concentration of both phase I metabolites was only 5%
of that of the parent compound. Pharmacokinetics of the monohydrolysis
product of bendamustine did not differ in both groups. Leukopenia,
thrombocytopenia (nadirs on day 21) and lymphopenia (nadir on day
7) were significantly induced in HCC patients. Eleven of them had
grade 3 and 4 lymphopenia. Non-haematological toxicity was mild
and not significantly different between both groups. The most frequently
reported adverse events associated with bendamustine treatment were
dry mouth (68%), nausea (44%) and dysgeusia (24%).
Based on these data, we would suggest a stepwise dose reduction
up to 30-40% in subjects with moderately to strongly impaired liver
function related to serum total bilirubin levels in the range from
1.3 to 3.0 mg/dl.
(1) Teichert J, Sohr R, Baumann F, Hennig L, Merkle K, Caca K and
Preiss R (2005) Drug Metab Dispos 33: 984-992
(2) Teichert J, Sohr R, Hennig L, Baumann F, Schoppmeyer K, Patzak
U, Preiss R (2009) Drug Metab Dispos 37: 292-301
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