Page 1025 - Hematology_ Basic Principles and Practice ( PDFDrive )

908 Part VII Hematologic Malignancies

itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, concentration of bortezomib was 509 ng/mL (range: 109–1300 ng/
telithromycin, ritonavir, indinavir, nelfinavir, voriconazole, amprena- mL). The mean elimination half-life of bortezomib after the first dose
vir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, ranged from 9 to 15 hours at doses ranging from 1.45 to 2.00 mg/
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diltiazem, grapefruit, grapefruit juice, or St. John’s wort. Everolimus m in patients with advanced malignancies. In vitro studies with
concentrations are decreased when administered with strong CYP3A4 human liver microsomes and human cDNA-expressed cytochrome
inducers such as phenytoin, carbamazepine, rifampin, rifabutin, P450 isozymes indicate that bortezomib is primarily oxidatively
rifapentine, or phenobarbital. metabolized via cytochrome P450 enzymes 3A4, 2D6, 2C19, 2C9,
and 1A2. The major metabolic pathway is deboronation to form two
Therapeutic Indications in Hematology: Everolimus has been deboronated metabolites that subsequently undergo hydroxylation to
used in MCL, diffuse large B-cell lymphoma, and Hodgkin several inactive metabolites.
lymphoma.
Preparation and Administration: Bortezomib for injection is
Arsenic Trioxide supplied as a lyophilized powder for reconstitution. Each sterile
single-use vial contains 3.5 mg of bortezomib and 35 mg of man-
Chemistry and Mechanism of Action: The mechanism of nitol, USP. Each vial is reconstituted with 3.5 mL normal (0.9%)
action of arsenic trioxide is not completely understood. Arsenic tri- saline such that the reconstituted solution contains bortezomib at a
oxide causes morphologic changes and DNA fragmentation charac- concentration of 1 mg/mL. The pH of the reconstituted solution is
teristic of apoptosis in NB4 human promyelocytic leukemia cells in between 5 and 6. The drug is given without any further dilution as
vitro, possibly mediated by activation of cysteine proteases (caspases). an IV bolus over 3–5 seconds. Intact vials of lyophilized bortezomib
Arsenic trioxide also causes damage or degradation of the fusion for injection are stored in a refrigerator at 2–8°C (35–47°F) and
protein PML-RARβ. protected from light. Stability studies are ongoing to monitor each
clinical lot. Product should be administered immediately after recon-
Absorption, Fate, and Excretion: The metabolism of arsenic stitution. The solution as reconstituted is stable for 43 hours at room
trioxide involves reduction of pentavalent arsenic to trivalent arsenic temperature. Bortezomib is administered as an IV bolus (over 3–5
by arsenate reductase and methylation of trivalent arsenic to mono- seconds) twice weekly for 2 weeks followed by a 1-week rest period.
methylarsinic acid and monomethylarsinic acid to dimethylarsinic
acid by methyltransferases. The main site of methylation reactions Toxic Effects: The most commonly reported adverse events are
appears to be the liver. The pharmacokinetics of trivalent arsenic, the asthenic conditions (including fatigue, malaise, and weakness; 65%),
active species, have not been characterized. nausea (64%), diarrhea (51%), decreased appetite (including anorexia;
43%), constipation (43%), thrombocytopenia (43%), peripheral
Preparation and Administration: Arsenic trioxide is available in neuropathy (including peripheral sensory neuropathy and peripheral
10-mL, single-use ampules containing 10 mg of arsenic trioxide. It neuropathy aggravated; 37%), pyrexia (36%), vomiting (36%), and
is formulated as a sterile, nonpyrogenic, clear solution of arsenic anemia (32%). Fourteen percent of patients experienced at least one
trioxide in water for injection using sodium hydroxide and dilute episode of grade 4 toxicity, with the most common being thrombo-
hydrochloric acid to adjust to pH 8. Trisenox should be diluted with cytopenia (3%) and neutropenia (3%).
100–250 mL of 5% dextrose injection, USP, or 0.9% sodium chlo-
ride injection, USP. Arsenic trioxide should be administered IV over Potential Drug Interactions: No formal drug interaction studies
1–2 hours. The infusion duration may be extended up to 4 hours if have been conducted with bortezomib. In vitro studies with human
acute vasomotor reactions are observed. A central venous catheter is liver microsomes indicate that bortezomib is a substrate of cyto-
not required. chrome P450 3A4, 2D6, 2C19, 2C9, and 1A2. Bortezomib may
inhibit 2C19 activity (IC 50 = 18 µM, 6.9 µg/mL) and increase
Toxic Effects: Arsenic trioxide has electrocardiographic abnormali- exposure to drugs that are substrates for this enzyme. Patients who
ties, including QT interval prolongation, T-wave flattening, and atrio- are concomitantly receiving bortezomib and drugs that are inhibitors
ventricular block. Nonspecific edema and weight gain have been or inducers of cytochrome P450 3A4 should be closely monitored
reported. Dry skin, pruritus, and rashes have occurred relatively fre- for either toxicities or reduced efficacy. Patients on oral antidiabetic
quently. Anemia, thrombocytopenia, and neutropenia are also observed. agents receiving bortezomib treatment may experience hypo- or
hyperglycemia and require close monitoring of their blood glucose
Drug Interactions: Arsenic trioxide can cause QT interval prolon- levels and adjustment of the dose of their antidiabetic medication.
gation and complete atrioventricular block. QT prolongation can Finally, patients should be cautioned about the use of concomitant
lead to a torsade de pointes–type ventricular arrhythmia. The risk of medications that may be associated with peripheral neuropathy (e.g.,
torsade de pointes is related to the extent of QT prolongation, and amiodarone, antivirals, isoniazid, nitrofurantoin, or statins), or with
concomitant administration of QT-prolonging drugs may exacerbate a decrease in blood pressure.
this phenomenon.
Therapeutic Indications in Hematology: Bortezomib is
Therapeutic Indications in Hematology: Arsenic trioxide is approved by the US Food and Drug Administration (FDA) for the
effective in newly diagnosed acute promyelocytic leukemia, FAB M3. initial treatment of MM patients.
Moreover, in patients who are refractory to or have relapsed from
retinoid and anthracycline chemotherapy, arsenic trioxide has some Carfilzomib
activity as a single agent for relapsed or refractory MM. Arsenic tri-
oxide produced hematologic improvement in a subset of patients with Chemistry and Mechanism of Action: Carfilzomib is an
MDS. epoxomicin derivate that irreversibly binds to and inhibits the
chymotrypsin-like activity of the 20S proteasome. Inhibition of
Bortezomib (Velcade) proteasome-mediated proteolysis results in an accumulation of polyu-
biquinated proteins, which may lead to cell cycle arrest, induction of
Molecular Formula: The molecular formula is C 19H 25BN 4O, apoptosis, and inhibition of tumor growth.
molecular weight 384.24 g/mol, N-pyrazinecarbonyl-L-phenylalanine-
L-leucine boronic acid. Absorption, Fate, and Excretion: Carfilzomib is an investiga-
tional product. It has rapid clearance with an elimination half-life of
Absorption, Fate, and Excretion: After IV administration of a less than 30 minutes and a clearance higher than liver blood flow,
2
1.3-mg/m dose, the median estimated maximum plasma which suggests there are multiple clearance pathways.