Page 1018 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 901

accounts for approximately 30% of active drug elimination and continuous infusion schedules. Other less common and mild toxici-
appears to be of greater importance. The half-life is quite variable, ties include nausea, vomiting, diarrhea, fever, fatigue, alopecia, skin
with a range of 23–42 hours. Patients with severe hepatic dysfunction rash, and increased liver function tests. Mucositis has been seen with
have been shown to eliminate the drug more slowly. prolonged infusion schedules over 5 days or when topotecan is given
in higher doses.
Preparation and Administration: Mitoxantrone is commercially
available as a 2-mg/mL solution in 10-mL, 12.5-mL, and 15-mL vials Potential Drug Interactions: In vitro data suggest that there may
(20, 25, and 30 mg per vial, respectively). The drug is further diluted be some synergism if a topoisomerase I inhibitor is given before a
in normal saline or 5% dextrose in water for injection and is admin- topoisomerase II inhibitor. In vitro data also suggest that synergism
istered for approximately 15–30 minutes into the tubing of a freely may be seen if a topoisomerase I inhibitor (topotecan) is given after
running IV infusion. As with the anthracyclines, erythema or streak- an alkylating agent, suggesting that topoisomerase I may be involved
ing along the vein of infusion indicates that the drug is being infused in the repair of alkylator-induced DNA damage.
too rapidly. Although mitoxantrone is not a vesicant, there have been
rare reports of tissue necrosis after extravasation. Therapeutic Indications in Hematology: Phase II studies
suggest that topotecan has activity in MDS, AML, and MM.
Toxic Effects: Myelosuppression, principally leukopenia, is the
dose-limiting toxic effect. Thrombocytopenia is relatively mild. Irinotecan (Camptosar or CPT-11)
Nausea, vomiting, and alopecia are usually mild and occur in fewer
than 30% of patients treated. Rarely, mucositis and elevation of liver Chemistry and Mechanism of Action: Irinotecan (Camptosar
enzymes occur. The drug imparts a blue color to the urine of patients or CPT-11) is a prodrug that has a bulky piperidino side chain at
treated. One of the primary advantages of mitoxantrone, compared C-10 that is cleaved in vivo by a carboxylesterase-converting enzyme
with doxorubicin, is its reduced incidence of cardiac toxicity. Occa- to generate SN-38. SN-38 is approximately 1000-fold more potent
sionally, patients develop congestive heart failure after treatment with a topoisomerase I inhibitor than CPT-11. The lactone forms of both
mitoxantrone in the absence of prior anthracycline exposure, although SN-38 and CPT-11 are more potent inhibitors of topoisomerase I
the incidence appears to be less than 5%. than the carboxylate forms, which is felt to be the mechanism of
action of these drugs as described for topotecan.
Potential Drug Interactions: None reported.
Absorption, Fate, and Excretion: The terminal half-life of the
Therapeutic Indications in Hematology: Mitoxantrone is lactone form of CPT-11 is 7 hours, and that of the total drug is 10.5
approved for induction therapy of AML in adults. hours. The terminal half-life of SN-38 lactone is 8.7 hours, and that
of the total drug is 14.7 hours. Of a dose of irinotecan, 22% is
excreted unchanged in the urine. SN-38 is excreted into the bile and
TOPOISOMERASE I INHIBITORS can undergo glucuronidation. Whereas the plasma protein binding
of CPT-11 is reported to be between 30% and 68%, that of SN-38
Topotecan (Hycamtin) is 95%.
Chemistry and Mechanism of Action: Topotecan is a semisyn- Preparation and Administration: Irinotecan is available as a
thetic derivative of camptothecin that stabilizes a complex between 100-mg single-dose vial with 20 mg/mL of irinotecan. This prepara-
DNA topoisomerase I and DNA. The cytotoxic effect of this drug is tion also contains 45 mg of sorbitol/mL and 0.9 mg of lactic acid/
believed to result from the collision of DNA replication forks with a mL with the pH adjusted to 3.5. This solution can be diluted with
ternary complex of topoisomerase I, DNA, and topotecan. The 5% dextrose in water (preferred) or in normal saline to a final con-
resulting double-strand DNA breaks are lethal. The lactone form of centration of 0.1–1.2 mg/mL. The solution is stable for up to 24
topotecan, which predominates at an acidic pH, is a much more hours at room temperature or 48 hours when refrigerated. The dose
potent inhibitor of DNA topoisomerase I. should be modified for severe diarrhea.

Absorption, Fate, and Excretion: At neutral or physiologic pH Toxic Effects: The major toxic effect of irinotecan is diarrhea. This
the carboxylate form of topotecan is favored, and at a pH of less than can be early-onset diarrhea, occurring within hours of administration,
7 the lactone form is favored. Topotecan has been given as a bolus or or during the infusion, which can be associated with cramping,
by continuous infusion. In less than 1 hour after infusion, most of vomiting, flushing, and diaphoresis. These side effects are attributable
the circulating drug in the plasma is in the carboxylate form as a to the cholinergic effects of CPT-11 and can be managed with
result of the physiologic pH. Whereas the terminal half-life of the atropine. Severe later onset diarrhea can be treated with high-dose
lactone form of this S-phase–specific agent is 2.6 hours, the terminal loperamide, which has been found to decrease the incidence of grade
half-life of the total drug is 3.3 hours. In an IV dose, 36% is excreted 4 diarrhea from 20% to 2%. Diarrhea has been found to be the
unchanged in the urine, and there is a 1.5-fold concentration of the dose-limiting toxicity when irinotecan is given on a weekly schedule,
drug in bile. Cerebrospinal fluid levels of topotecan lactone reach and neutropenia is the dose-limiting toxicity when the drug is given
approximately 32% of plasma levels. Dose adjustment is required for every 3 weeks. Also seen are alopecia, nausea, vomiting, mucositis,
creatinine clearance less than 60 mL/min, but no adjustment is neces- fatigue, increased liver function test results, and rare cases of pulmo-
sary for bilirubin up to 10 mg/dL. nary toxicity.
Preparation and Administration: Topotecan is commercially Potential Drug Interactions: As described for topotecan, in vitro
available as 4-mg vials that are reconstituted with 4 mL of sterile data suggest some synergism when topoisomerase I inhibitors precede
water. This solution can be further diluted in normal saline or 5% topoisomerase II inhibitors or follow alkylating agent
dextrose in water and should be used immediately. administration.

Toxic Effects: The dose-limiting toxicity for topotecan for all Therapeutic Indications in Hematology: Phase I and phase II
schedules is neutropenia. Thrombocytopenia and anemia are less studies have shown responses in refractory leukemia and
common, although there is an increase in thrombocytopenia with lymphoma.