Page 1028 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 911

basis, glucocorticoids also may induce a “Cushingoid” appearance, Fate, Absorption, and Excretion: Tanespimycin has a mean
easy bruisability, peptic ulcers, osteoporosis, subcapsular cataracts, terminal half-life of 2.3 hours and is primarily metabolized by liver
and an increased susceptibility to infections related to impaired cel- microsomal enzymes, specifically CYP3A4. One metabolite, 17-AG,
lular immunity. Because of this, H 2 blockers, antifungal agents (e.g., is known to be active and has a mean terminal half-life of 4.6 hours.
ketoconazole), and sulfamethoxazole–trimethoprim have been used Peak plasma concentrations of 17-AAG and 17-AG occur at 30 and
in certain glucocorticoid chemotherapy combinations. 60 minutes, respectively. 10.6% of 17-AAG and 7.8% of 17-AG is
recovered in the urine over a 72-hour period.
Potential Drug Interactions: Glucocorticoids interact with a
variety of drugs, including barbiturates, oral contraceptives, erythro- Preparation and Administration: Tanespimycin is available as a
mycin, hydantoins, rifampin, isoniazid, and salicylates. Given the single-use amber vial containing 50 mg of tanespimycin in 2 mL of
wide range of doses of glucocorticoids used, however, these interac- dimethylsulfoxide. Before administration, the tanespimycin concen-
tions are of no major clinical relevance. trate must be completely thawed at room temperature (over a period
of ≤1 hour). Incomplete thawing affects the concentration of the drug
Clinical Indications in Hematology: Glucocorticoids have because of changes in volume. Tanespimycin concentrate must be
direct anticancer activity in many hematologic malignancies, includ- diluted to 1 mg/mL by withdrawing 2 mL and adding it to 48 mL
ing ALL, CLL, Hodgkin lymphoma, NHL, and plasma cell neo- of EPL diluent 2% egg phospholipids with 5% dextrose in water. A
plasms. Because of their efficacy and toxic profiles, which do not clear solution should be obtained with gentle mixing. Shaking should
overlap with the toxic effects of the other cytotoxic agents, glucocor- be avoided to prevent foaming. No further dilution is required and
ticoids are used in many chemotherapy regimens. In addition, they the final solution should be dispensed in a glass bottle. A 0.45-µm
are useful in the management of hypercalcemia secondary to myeloma filter may be used, but is not required. The infusion should be
and lymphomas, and are of paramount importance in the treatment completed within 8 hours of mixing. Intact vials of Tanespimycin
of autoimmune hematologic disorders. should be stored in the freezer (–10° to –20°C). EPL diluent should
be stored in the refrigerator (2°–8°C) and not frozen. Administration
Flavopiridol is by IV infusion.

Chemistry and Mechanism of Action: Flavopiridol is a semi- Toxicity: Anemia, diarrhea, nausea, vomiting, fatigue, transamini-
synthetic flavone and selective inhibitor of CDKs 1, 2, 4–7, PKC, tis, and muscle pain.
PKA, and PDGF causing cell cycle arrest. It also may inhibit CDK9/
TEFb, which causes downregulation of McI-1, BIRC4, cyclin D1, Drug Interactions: Tanespimycin is metabolized by CYP3A4.
and p21CIP1. Agents that alter CYP3A4 activity may affect drug levels and metabo-
lism, although this has not been shown to affect clinical use.
Absorption, Fate, and Excretion: Flavopiridol is 94% protein
bound and is metabolized by the UDP glucuronyltransferase isoen- Therapeutic Uses: Lymphoma and leukemia in clinical trials.
zymes. Its half-life varies with infusion duration and ranges from 3.5
hours (1-hour infusion) to 27 hours (72-hour infusion). Imatinib (Gleevec)
Preparation and Administration: Flavopiridol is supplied as a Chemistry and Mechanism of Action: Imatinib, a phenylami-
10-mg/mL yellow-greenish solution in a 5-mL vial. Contents may be nopyrinadine derivative, is a selective protein TK inhibitor effecting
diluted in either 5% dextrose injection or 0.9% sodium chloride BCR-ABL TK. This enzyme is found commonly in chronic myeloid
injection to achieve a final concentration of 0.09–1 mg/mL. If the leukemia and in some clones of ALL. Imatinib also inhibits the
drug is administered through peripheral IV access, a concentration kinases for PDGF, SCF, and KIT.
of less than 0.5 mg/mL is thought to decrease thrombotic complica-
tions. Flavopiridol has been administered as a 1-, 24-, and 72-hour Absorption, Fate, and Excretion: Imatinib is well absorbed and
infusion. achieves peak levels within 2–4 hours and follows linear pharmaco-
kinetics at the standard doses. Cytochrome P450 is the major route
Toxic Effects: Grade 4 neutropenia and grade 3 lymphocytopenia of metabolism, with CYP3A4 being the primary pathway. An
occur and are more common with shorter durations of infusion. N-desmethyl piperazine is the main metabolite and is active. Pediatric
Thrombocytopenia is seen infrequently. Secretory diarrhea is a dose- patients follow the same pharmacokinetics as in adults.
limiting toxicity and may last for up to 3 days. Orthostatic hypoten-
sion is a frequently seen occurrence. Thrombosis with the 72-hour Preparation and Administration: Imatinib is available in a
infusion duration was far more common than in the shorter infusion film-coated tablet. In its pure form, it is a white to brownish to
durations. A fatigue rate approaching 75% has been reported. Other yellowish powder and is soluble in aqueous buffers of less than 5.5.
toxicities include pleuritic chest pain, hyperbilirubinemia, and
nausea. Toxic Effects: Gastrointestinal effects are common and include
nausea and diarrhea. Muscle cramps are seen in one-third of patients
Potential Drug Interactions: Paclitaxel in combination with receiving imatinib. Myelosuppression reflected as thrombocytope-
flavopiridol has been associated with severe dose-limiting nia, anemia, and neutropenia occurs, with thrombocytopenia and
neutropenia. neutropenia seen more frequently in patients in accelerated phase
or blast crisis. Fluid retention is dose related and is exhibited as
Therapeutic Indications in Hematology: Flavopiridol’s place edema and weight gain, but pleural and pericardiac effusions are also
in therapy is still being assessed. It has activity and use in hematologic seen. Fatigue and headache, although low grade, occur in 25% of
malignancies, including MCL, leukemias, and MM. It may cause patients.
potential solid tumors in combination with other agents. The FDA
has granted orphan drug status for flavopiridol to treat patients with Potential Drug Interactions: Drugs that inhibit CYP3A4 may
AML. increase imatinib plasma concentrations; these include ketoconazole,
itraconazole, erythromycin, and clarithromycin. CY3A4 inducers
Tanespimycin (17-AAG, Geldanamycin, NSC 330507) that may decrease plasma concentration of CY3A4 are dexametha-
sone, rifampin, phenytoin, and carbamazepine. Imatinib increases
Chemistry: Tanespimycin is a water-soluble benzoquinone ansamy- concentrations of simvastatin, cyclosporine, and warfarin, along with
cin antibiotic that binds to HSP90. other medications that are metabolized by CYP3A4.