Page 1020 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 903

Carboplatin leads to less emesis than cisplatin. Although nausea and dehydrated alcohol, USP. Romidepsin is administered IV over a
vomiting are common, they can be easily controlled with antiemetics. 4-hour infusion.
At high doses such as those used for bone marrow transplantation,
hepatotoxicity, renal dysfunction, and moderate-to-severe cytotoxic- Toxic Effects: Romidepsin is associated with cardiac toxicities
ity can occur. including ST-segment changes and T-wave changes, along with QT
prolongation, hypotension and ventricular arrhythmia, severe myelo-
Potential Drug Interactions: None reported. suppression along with gastrointestinal symptoms, and TLS.

Clinical Indications in Hematology: Carboplatin has been Potential Drug Interactions: All drugs undergoing metabolism
recently approved for the treatment of ovarian cancer. It is also used by the CYP3A and CYP2D6 pathways should be used with
to treat small-cell lung, testicular, head and neck, and genitourinary caution.
cancers. High-dose carboplatin is presently under evaluation in acute
leukemias and lymphomas. Therapeutic Indications in Hematology: Cutaneous and
peripheral T-cell lymphomas.
HISTONE DEACETYLASE INHIBITORS
TYROSINE KINASE INHIBITORS
Panobinostat
Bosutinib
Chemistry and Mechanism of Action: Panobinostat is a histone
deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of Chemistry and Mechanism of Action: Bosutinib is a TK
HDACs at nanomolar concentrations. HDACs catalyze the removal inhibitor, specifically BCR-ABL kinase.
of acetyl groups from the lysine residues of histones and some non-
histone proteins. Inhibition of HDAC activity results in increased Absorption, Fate, and Excretion: Bosutinib is primarily
acetylation of histone proteins, an epigenetic alteration that results in metabolized by CYP3A4. The major circulating metabolites identi-
a relaxing of chromatin, leading to transcriptional activation. In vitro fied in plasma are oxydechlorinated (M2) bosutinib (19% of parent
panobinostat caused the accumulation of acetylated histones and exposure) and N-demethylated (M5) bosutinib (25% of parent
other proteins, inducing cell cycle arrest and/or apoptosis of some exposure), with bosutinib N-oxide (M6) as a minor circulating
transformed cells. Panobinostat shows more cytotoxicity towards metabolite. All the metabolites were deemed inactive. The half life of
tumor cells compared with normal cells. bosutinib is 22.5 hours and 95% is protein bound. Food increases
the absorption of bosutinib. The bosutinib dose should be reduced
Absorption, Fate, and Excretion: The oral bioavailability of in patients with severe (creatinine clearance [CLcr] <30 mL/min) or
panobinostat is approximately 21%, and is 90% bound to human moderate (CLcr 30–50 mL/min) renal impairment.
plasma proteins and is independent of concentration. Panobinostat
is metabolized in the liver via reduction, hydrolysis, oxidation, and Preparation and Administration: Bosutinib is available as a
glucuronidation. About 40% of hepatic elimination occurs via 100-mg yellow oval and a 500-mg red oval tablet.
CYP3A, while CYP2D6 and CYP2C19 are minor pathways.
Toxic Effects: Bosutinib is associated with gastrointestinal toxicity
Preparation and Administration: Panobinostat is available as a including diarrhea, nausea, vomiting, abdominal pain, myelosuppres-
10-mg size #3 light-green opaque capsule, a 15-mg size #1 orange sion, and hepatic transaminase elevations. Fluid retention occurs with
opaque capsule, and a 20-mg size #1 red opaque capsule. bosutinib and may manifest as pericardial effusion, pleural effusion,
pulmonary edema, and/or peripheral edema.
Toxic Effects: Panobinostat has been associated with severe diar-
rhea, severe and fatal cardiac ischemic events, severe arrhythmias, Potential Drug Interactions: All drugs undergoing metabolism
serious hemorrhage, myelosuppression, and elevations in aminotrans- by the CYP3A4 pathway should be used with caution.
ferases and total bilirubin.
Therapeutic Indications in Hematology: Philadelphia
Potential Drug Interactions: All drugs undergoing metabolism chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
by the CYP3A and CYP2D6 pathways should be used with
caution. Crizotinib
Therapeutic Indications in Hematology: Multiple myeloma. Chemistry and Mechanism of Action: Crizotinib is an inhibi-
tor of RTKs including ALK, hepatocyte growth factor receptor
Romidepsin (c-Met), reactive oxygen species 1 (c-ros), and Recepteur d’Origine
Nantais (RON). Crizotinib prevents the expression of oncogenic
Chemistry and Mechanism of Action: Romidepsin is a HDAC fusion proteins from activating gene expression. This inhibition
inhibitor. HDAC catalyzes the removal of acetyl groups from acety- impairs cell proliferation and survival of these proteins.
lated lysine residues in histones, resulting in the modulation of gene
expression, which induces cell cycle arrest and apoptosis. Absorption, Fate, and Excretion: Bioavailability ranges from
32% to 66%. Crizotinib is metabolized in the liver by CYP3A4/5.
Absorption, Fate, and Excretion: Romidepsin undergoes The primary pathways include oxidation of the piperidine ring to
extensive metabolism primarily by CYP3A4, with minor contribu- crizotinib lactam and O-dealkylation, with subsequent phase 2 con-
tion from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. It has a jugation of O-dealkylated metabolite. No starting dose adjustment is
3-hour half life and is >90% protein bound. needed for patients with mild (CLcr 60–89 mL/min) or moderate
(CLcr 30–59 mL/min) renal impairment based on a population
Preparation and Administration: Romidepsin is supplied as a pharmacokinetic analysis. Increased exposure to crizotinib occurred
kit including a sterile, lyophilized powder in a single-use vial contain- in patients with severe renal impairment (CLcr <30 mL/min) not
ing 10 mg of romidepsin and 20 mg of the bulking agent, povidone, requiring dialysis. Administer XALKORI at a dose of 250 mg PO
USP. In addition, each kit includes one sterile diluent vial containing once daily in patients with severe renal impairment not requiring
2 mL (deliverable volume) of 80% propylene glycol, USP, and 20% dialysis.