Page 1006 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 889

carboxamide (MTIC), which is also the active methyl group–donating Bendamustine
metabolite of DTIC. Unlike DTIC, formation of MTIC from
temozolomide does not require metabolic activation (liver); thus Chemistry and Mechanism of Action: Bendamustine is a
there is much more consistent conversion from temozolomide to the bifunctional alkylating agent (mechlorethamine analogue). Its struc-
methyl-donating MTIC. The cytotoxicity of MTIC is thought to be ture is characterized by a nitrogen mustard group linked to a benz-
primarily caused by alkylation of DNA. Alkylation (methylation) imidazole nucleus, which forms covalent bonds with electron-rich
7
6
occurs mainly at the O and N positions of guanine. Cytotoxicity nucleophilic moieties, resulting in interstrand DNA cross-links.
results from processing of these lesions by methylguanine methyl- Bendamustine is active against both quiescent and dividing cells.
transferase, mismatch repair, and base excision repair.
Absorption, Fate, and Excretion: Although absorbed well
Absorption, Fate, and Excretion: Temozolomide is rapidly and orally, bendamustine is only administered intravenously. It is highly
completely absorbed after oral administration; peak plasma concen- protein bound, averaging approximately 95%. The half-life of benda-
trations occur in 1 hour. Food reduces the rate and extent of temo- mustine is approximately 40 minutes. Bendamustine is primarily
zolomide absorption. metabolized in the liver via hydrolysis, and little is excreted in urine
Temozolomide exhibits a mean elimination half-life of 1.8 hours unchanged, but the pharmacokinetics in patients with significant
and exhibits linear kinetics over the therapeutic dosing range. Temo- renal failure are unknown.
zolomide is spontaneously hydrolyzed at physiologic pH to the active
species, MTIC and to temozolomide acid metabolite. MTIC is Preparation and Administration: Bendamustine is available for
further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), IV use in single-use vials containing either 25 mg or 100 mg of
which is known to be an intermediate in purine and nucleic acid bendamustine HCl. Sterile water for injection is added to each vial
biosynthesis and to methylhydrazine, which is believed to be the to obtain a 5-mg/mL solution. The lyophilized powder should
active alkylating species. Approximately 38% of the administered completely dissolve in 5 minutes. After being diluted with either
temozolomide total radioactive dose is recovered over 7 days; 37.7% 0.9% sodium chloride injection, US Pharmacopeia (USP), or 2.5%
in urine and 0.8% in feces. The majority of the recovery of radioactiv- dextrose/0.45% sodium chloride injection, USP, the final admixture
ity in urine is as unchanged temozolomide (5.6%), AIC (12%), is stable for 24 hours when stored refrigerated or for 3 hours when
temozolomide acid metabolite (2.3%), and unidentified polar stored at room temperature.
metabolite(s) (17%). Overall clearance of temozolomide is approxi-
2
mately 5.5 L/hour/m . Toxic Effects: Bendamustine frequently causes anemia, severe
neutropenia, and thrombocytopenia. Infusion reactions presenting as
Preparation and Administration: Temozolomide is given orally fever, chills, pruritus, and rash have been seen. Antihistamines,
with each capsule containing either 5, 20, 100, 140, 180, or 250 mg antipyretics, and corticosteroids have been effective in preventing
of temozolomide. The inactive ingredients for TEMODAR capsules these reactions. Tumor lysis syndrome has been seen with the first
are lactose anhydrous, colloidal silicon dioxide, sodium starch glyco- dose of bendamustine, so appropriate precautions should be taken.
late, tartaric acid, and stearic acid. Local reactions are seen with extravasation, and care should be taken
when administering the drug in a peripheral site. Headache, nausea,
Toxic Effects: Bone marrow depression, including neutropenia, and vomiting, as well as skin reactions including rash, toxic skin
lymphopenia, anemia, and thrombocytopenia, occurs frequently with reactions, and bullous exanthema, have occurred with bendamustine.
temozolomide. Mild transaminase elevations of up to 40% of patients AML has been reported in patients after use of bendamustine HCl.
and hyperbilirubinemia of up to 19% are seen. Mild-to-moderate
headache is among the most commonly reported adverse effects along Drug Interactions: Although their clinical significance is unknown,
with moderate nausea and vomiting, although these may be second- ciprofloxacin, fluvoxamine, and omeprazole may increase bendamus-
ary to the use of antiemetics. tine levels and decrease levels of active minor metabolites.
Drug Interactions: None described. Therapeutic Indications in Hematology: Bendamustine has
been effective in treating chronic lymphoid leukemia, MM, Hodgkin
Therapeutic Indications in Hematology: Temozolomide may lymphoma, NHL, and indolent B-cell lymphomas.
have some activity in both acute myeloid leukemia (AML) and acute
lymphocytic leukemia (ALL), but the correct dose is presently
unknown. Temozolomide has no activity in NHL.