DESCRIPTION
Carfilzomib
Mechanism of Action
• Tetrapeptide epoxyketone proteasome inhibitor of the 26S proteasome.
• Binds to the N-terminal threonine-containing active sites of the 20S
proteasome, the proteolytic core within the 26S proteasome.
• The 26S proteasome is a large protein complex that degrades ubiquinated
proteins. This pathway plays an essential role in regulating the
intracellular concentrations of various cellular proteins.
• Inhibition of the 26S proteasome prevents the targeted proteolysis of
ubiquinated proteins, and disruption of this normal pathway can affect
multiple signaling pathways within the cell, leading to cell death.
• Results in downregulation of the NF-κB pathway. NF-κB is a transcription
factor that stimulates the production of various growth
 factors, including IL-6, cell adhesion molecules, and antiapoptotic
proteins, all of which contribute to cell growth and chemoresistance.
• Can overcome resistance to bortezomib.
• Displays in vitro growth inhibitory activity in both solid tumors and
hematologic malignancy cancer cells.
Mechanism of Resistance
Increased expression of the multidrug-resistant gene with elevated
P170 protein, leading to increased drug efflux and decreased intracellular
accumulation.
Absorption
Carfilzomib is given only by the IV route.
Distribution
Mean steady-state volume of distribution is 28 L. Based on in vitro testing,
about 97% of drug bound to plasma proteins.
Metabolism
Carfilzomib is rapidly and extensively metabolized by peptidase cleavage
and epoxide hydrolysis. The metabolites have no documented antitumor
activity. Liver P450-mediated mechanisms play a relatively minor role in
drug metabolism. Carfilzomib is rapidly cleared with a half-life of about 1
hour on day 1 of cycle 1.
Indications
FDA-approved for the treatment of patients with multiple myeloma who
have received at least two prior therapies, including bortezomib and an
immunomodulatory therapy.
Dosage Range
Recommended dose for cycle 1 is 20 mg/m2/day and if tolerated, the dose
can be increased to 27 mg/m2/day for cycle 2 and all subsequent cycles.
Carfilzomib is administered by IV on 2 consecutive days each week for 3 weeks
(days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period (days 17–28).
Drug Interactions
None have been well characterized to date.
Special Considerations
1. Closely monitor for cardiac complications. Patients with prior history
of MI in the preceding 6 months, congestive heart failure (CHF),
and conduction system abnormalities not controlled by medication
may be at increased risk for cardiac complications.
2. Closely monitor pulmonary status given the risk of pulmonary arterial
hypertension and pulmonary complications.
3. Monitor for infusion-related events, which can occur immediately
following or up to 24 hours after drug administration. Premedication
with dexamethasone 4 mg PO or IV prior to all doses of carfilzomib
during cycle 1 and prior to all doses during the first cycle of dose
escalation has been shown to reduce the incidence and severity of
infusion reactions.
4. Patients should be well hydrated prior to drug administration to
reduce the risk of renal toxicity.
5. Patients with high tumor burden are at increased risk for developing
tumor lysis syndrome.
6. Monitor CBCs routinely as carfilzomib therapy is associated with
thrombocytopenia with nadirs occurring at around day 8 of each
28-day cycle.
7. Monitor LFTs on a routine basis as hepatotoxicity and rare cases of
hepatic failure have been reported with carfilzomib.
8. Pregnancy category D. Breastfeeding should be avoided.
Toxicity 1
Fatigue and generalized weakness.
Toxicity 2
Cardiac toxicity with CHF, MI, and rare cases of cardiac arrest.
Toxicity 3
Myelosuppression with thrombocytopenia, neutropenia, and anemia.
Toxicity 4
Pulmonary arterial hypertension. Rare event observed in 2% of patients.
Toxicity 5
Pulmonary toxicity presenting as dyspnea in up to 35% of patients.
Toxicity 6
Hepatotoxicity with elevations in serum transaminases (SGOT, SGPT).
Drug-induced hepatotoxicity with fatal outcomes has been reported.
Toxicity 7
Fever (.388C) is relatively common.
Toxicity 8
Orthostatic hypotension.
SPECIFICATION
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