Page 1026 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 909

Preparation and Administration: Carfilzomib currently is avail- Drugs that induce CYP3A4 activity may decrease dasatinib plasma
able investigationally as an IV product. concentrations and decrease its effectiveness. The solubility of dasat-
inib is pH dependent. Simultaneous administration of SPRYCEL
Toxic Effects: Carfilzomib has been shown to produce mild-to- with antacids should be avoided, and there should be 2 hours’ separa-
moderate nausea and diarrhea. Respiratory symptoms occur and tion in the administration of dasatinib and antacids. Long-term
include cough, dyspnea, and exertional dyspnea. Neurologic symp- suppression of gastric acid secretion by H 2 blockers or proton pump
toms include hypoesthesia, headache, and paresthesia. Additional inhibitors may reduce dasatinib exposure, and antacids are preferred.
adverse events seen are fatigue, pyrexia, and peripheral edema. Dasatinib is a time-dependent inhibitor of CYP3A4; therefore,
CYP3A4 substrates may have their plasma concentration altered by
Drug Interactions: Data not available. dasatinib.
Therapeutic Indications in Hematology: Carfilzomib has been Therapeutic Indications in Hematology: Treatment with
approved by the FDA for the treatment of MM of patients who have dasatinib results in hematologic and cytogenetic responses in patients
received at least two prior therapies, Hodgkin lymphoma, and NHL. with lymphoid blast crisis, Ph+ chronic myeloid leukemia, and Ph+
ALL as initial treatment and in disease-resistant or intolerant to
Ibrutinib imatinib.

Chemistry and Mechanism of Action: Ibrutinib is a first-in- Bleomycin
class oral therapy that is a selective, irreversible inhibitor of Bruton
tyrosine kinase (BTK) and inhibits BTK activity, preventing B-cell Chemistry and Mechanism of Action: Bleomycin is a glyco-
activation and B-cell–mediated signaling, and inhibiting the growth peptide. Its antitumor effect correlates with its ability to cause scission
of malignant B cells that overexpress BTK. of both double- and single-stranded DNA via activated oxygen
formed by the iron–bleomycin complex. Bleomycin also affects DNA
Absorption, Fate, and Excretion: No data available. repair by inhibiting DNA ligase.

Preparation and Administration: Ibrutinib is an approved agent Absorption, Fate, and Excretion: Bleomycin is rapidly distrib-
available as an oral dose. uted throughout the body and concentrates in the skin, lungs,
kidneys, peritoneum, and lymph nodes. Its plasma half-life is 2–4
Toxic Effects: Ibrutinib may cause diarrhea, fatigue, nausea, and hours. Within 24 hours of injection, approximately 50% of an
skin bruising. Also, transient high lymphocyte counts are frequently administered dose is excreted unchanged in the urine. Bleomycin
seen. elimination correlates well with creatinine clearance; accordingly,
patients with renal failure should receive reduced doses. In the tissues,
Drug Interactions: No data available. bleomycin is inactivated by bleomycin hydrolase. Tissues lacking this
enzyme, such as the lungs and skin, are more susceptible to the drug’s
Therapeutic Indications in Hematology: Ibrutinib is used in toxic effects.
CLL/small lymphocytic lymphoma, MCL, diffuse large B-cell lym-
phoma, and MM. It is approved for the treatment of MCL patients Preparation and Administration: Bleomycin is commercially
who have received two prior therapies and CLL patients with the 17p available in vials containing 15 U (approximately equivalent to
deletion. 15 mg), from which it is reconstituted for injection with 3–5 mL of
sterile water, normal saline, 5% dextrose in water, or bacteriostatic
Dasatinib water. For IV infusion, the reconstituted solution can be further
diluted with either normal saline or 5% dextrose in water and
Chemistry and Mechanism of Action: Dasatinib is an orally administered over 5 minutes. Bleomycin can also be administered by
active TK inhibitor against BCR-ABL, SRC family, c-KIT, EPH the SC, IV, IM, intracavitary, and intraarterial routes. Because
receptor A2, and PDGFRβ. The primary mechanism of resistance to patients with lymphomas are at an increased risk of anaphylactoid
dasatinib is the T315I mutant clone. reactions, which may not occur until 12 hours after administration,
the first two doses should be IM “test doses” of 1–2 mg. If no reac-
Absorption, Fate, and Excretion: Dasatinib is orally absorbed tions occur, full doses may be given.
and extensively metabolized in human liver microsomes, primarily by
cytochrome P450 CYP3A4, to an active metabolite. CYP3A4 is the Toxic Effects: The most serious toxic effect is interstitial pneumo-
primary enzyme responsible for the formation of the active metabo- nitis, which is dose related and occurs in approximately 10% of
lite. Flavin-containing monooxygenase 3 and uridine diphosphate- patients treated with cumulative doses of greater than 350–400 U.
glucuronosyltransferase enzymes are also involved in the formation The interstitial pneumonitis may evolve into life-threatening pulmo-
of dasatinib metabolites. In human liver microsomes, dasatinib was nary fibrosis. Pulmonary toxicity is more common in patients older
a weak time-dependent inhibitor of CYP3A4. The exposure of the than 70 years, in those receiving a total dose of greater than 400 U,
active metabolite, which is equipotent to dasatinib, represents and in those who received prior radiotherapy to the lung. It is
approximately 5% of the dasatinib AUC. important to emphasize, however, that the pulmonary toxicity is
unpredictable; it has been reported in patients who had none of these
Preparation and Administration: Dasatinab is an oral agent risk factors and has occurred in a patient after administration of only
usually taken twice daily without regard to meals. 20 U. Some reports suggest that an increased concentration of
inspired oxygen acts synergistically with bleomycin to produce pul-
Toxic Effects: Treatment with dasatinib is associated with severe monary fibrosis. During critical illness and perioperatively, therefore,
thrombocytopenia, neutropenia, anemia, and platelet dysfunction. an attempt should be made to maintain the inspired oxygen concen-
Also seen is fluid retention, including pleural and pericardial effusion, tration at 21%. The early phases of the pulmonary toxicity are clini-
pulmonary edema, severe ascites, and generalized edema. A prolonged cally manifested by dyspnea and fine rales. Although corticosteroids
QT interval has been observed as well as extensive skin rashes. are often used in this setting, it is not clear that they are of benefit.
Mucocutaneous toxicity occurs in 50% of patients treated and is
Drug Interactions: Dasatinib is a CYP3A4 substrate. Administra- manifested by hyperpigmentation, pruritic erythema, mucositis,
tion with drugs that are CYP3A4 inhibitors may cause increased desquamation of the plantar surface skin of the hands or feet, ridging
dasatinib plasma concentrations and subsequent increase in toxicities. of the nails, and alopecia. The mucositis can be severe and is the acute