Page 1021 - Hematology_ Basic Principles and Practice ( PDFDrive )

904 Part VII Hematologic Malignancies

Preparation and Administration: Crizotinib is provided as a as well as undergoing metabolism by CYP3A4. None of the nilotinib
hard, 250-mg gelatin capsule, size 0, and a hard, 200-mg gelatin metabolites have significant pharmacologic activity.
capsule, size 1.
Preparation and Administration: Nilotinib is available in cap-
Toxic Effects: Rare but serious toxicities include hepatotoxic- sules for oral use, containing a 150- or 200-mg nilotinib base,
ity, interstitial lung disease/pneumonitis, QT prolongation, and anhydrous (as hydrochloride, monohydrate) with the following inac-
bradycardia. Other toxicities seen are vision disorders presenting as tive ingredients: colloidal silicon dioxide, crospovidone, lactose
visual impairment, photopia, blurred vision, sensory neuropathy, monohydrate, magnesium stearate, and polyoxamer 188.
renal cysts, nausea, vomiting and diarrhea, dizziness, and fluid
retention. Toxic Effects: Nilotinib may cause anemia, neutropenia, and
thrombocytopenia. Prolonged QT interval and sudden death has
Potential Drug Interactions: Co-administration of crizotinib occurred. Pruritus, rash, and nausea are common. Also seen with
with strong CYP3A inhibitors increases crizotinib plasma concentra- nilotinib are arthralgias and myalgias. Cough has also been associated
tions. Co-administration of crizotinib with strong CYP3A inducers with nilotinib.
decreases crizotinib plasma concentrations.
Drug Interactions: Nilotinib is a competitive inhibitor of cyto-
Therapeutic Indications in Hematology: ALK-positive ana- chrome P450 (CYP) isoenzymes 3A4, 2C8, 2C9, and 2D6, and
plastic large-cell lymphoma. has the potential to increase concentrations of drugs metabolized by
these enzymes. Nilotinib plasma concentration is increased during
Sorafenib concomitant use with potent CYP3A4 inhibitors (e.g., atazanavir,
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone,
Chemistry and Mechanism of Action: Sorafenib blocks Raf nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).
kinases, which are serine/threonine protein kinases that are down- Decreased nilotinib plasma concentration occurs during concomitant
stream effector molecules of Ras proteins. Theses kinases activate the use with potent CYP3A4 inducers (e.g., dexamethasone, carbamaze-
Raf/MEK/ERK signaling pathway mediating cell proliferation, dif- pine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s
ferentiation, and transformation. Sorafenib also inhibits tumor wort). Drugs that increase the pH of the upper gastrointestinal tract
angiogenesis by VEGF receptor (VEGFR)-2, VEGFR-3, PDGFRβ, may decrease the solubility of nilotinib and reduce its bioavailability.
Flt3, c-KIT, and p38-α. The oral administration of esomeprazole results in a 34% reduction
in the AUC of nilotinib.
Absorption, Fate, and Excretion: Bioavailability ranges from
38% to 49%. Sorafenib is metabolized through oxidative metabolism Therapeutic Indications in Hematology: Nilotinib has dem-
by CYP3A4 and glucuronidation with a mean elimination half-life onstrated activity in the case of CML resistance resulting from
of 25–48 hours. No correlation between sorafenib exposure and renal BCR-ABL kinase mutations from treatment with imatinib. This
function was observed following administration of a single PO dose includes accelerated-phase CML resistant or intolerant to prior
of 400 mg to subjects with normal renal function and subjects with therapy. ALL, Ph+, relapsed/refractory. Blastic phase chronic myeloid
mild (CLcr 50–80 mL/min), moderate (CLcr 30 to <50 mL/min), leukemia, Resistant or intolerant to imatinib. Chronic phase, Ph+,
or severe (CLcr <30 mL/min) renal impairment who were not on newly diagnosed. Chronic-phase CML, resistant or intolerant to
dialysis. No dose adjustment is necessary for patients with mild, prior therapy.
moderate, or severe renal impairment who are not on dialysis.
Ponatinib
Preparation and Administration: Tablets containing sorafenib
tosylate (274 mg) equivalent to 200 mg of sorafenib. Chemistry and Mechanism of Action: Ponatinib is a kinase
inhibitor that inhibits the in vitro TK activity of ABL and T315I mutant
Toxic Effects: Sorafenib has been associated with cardiac ischemia, ABL with IC 50 concentrations of 0.4 and 2.0 nM, respectively. Pona-
infarction hemorrhage, congestive heart failure and hypertension, tinib inhibits the in vitro activity of additional kinases with IC 50 con-
and QT interval prolongation. Adverse dermatologic effects includ- centrations between 0.1 and 20 nM, including members of the VEGFR,
ing hand-foot skin reaction, rash, Stevens-Johnson syndrome and PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT,
toxic epidermal necrolysis, gastrointestinal perforation, drug-induced RET, TIE2, and FLT3. The drug also inhibits the in vitro viability of
hepatitis, and impairment of TSH suppression in DTC have also cells expressing native or mutant BCR-ABL, including T315I.
been reported. Sorafenib also causes leukopenia, lymphopenia,
anemia, neutropenia, and thrombocytopenia. Absorption, Fate, and Excretion: Phase I (oxidative) and phase
II (hydrolysis) metabolism are involved in at least 64% of a ponatinib
Potential Drug Interactions: Any drug that has an effect on or dose. In phase I metabolism, CYP3A4 is primarily involved, with
is metabolized by CYP3A4 has potential interactions. CYP2C8, CYP2D6, and CYP3A5 involved to a lesser extent. Pona-
tinib is also metabolized by esterases or amidases. Ponatinib has a
Therapeutic Indications in Hematology: FLT3-ITD positive half-life of 24 hours.
AML.
Preparation and Administration: Ponatinib is provided as 15-
Nilotinib and 45-mg round white tablets.
Chemistry and Mechanism of Action: Nilotinib is a selective Toxic Effects: The use of ponatinib has led to arterial and venous
TK inhibitor active against BCR-ABL kinase. Nilotinib binds to and thrombosis and occlusions, including fatal myocardial infarction,
stabilizes the inactive conformation of the kinase domain of ABL stroke, and stenosis of large arterial vessels of the brain, and severe
protein. Nilotinib is 30-fold more potent than imatinib. peripheral vascular disease. Fatal and serious heart failure or left
ventricular dysfunction has occurred. Hypertension. Other toxicities
Absorption, Fate, and Excretion: Nilotinib is rapidly absorbed include peripheral neuropathy pancreatitis, ocular toxicity, serious
and reaches its peak concentration in 3 hours. The AUC of nilotinib bleeding events, fluid retention, and myelosuppression.
increases by 82% when given 30 minutes after a high-fat meal
compared with a fasting state. Its elimination half-life is approxi- Potential Drug Interactions: All drugs undergoing metabolism
mately 17 hours. It is metabolized by oxidation and hydroxylation, by the CYP3A4 pathway should be used with caution.