Highly selective eopxyketone proteasome inhibitor with minimal affinity for non-target proteases.

Kyprolis trade name.

Irreversible proteasome inhibitor.

A tetrapeptide epoxyketone proteosome inhibitor that selectively and irreversible binds to the N terminal threonine containing active sites of the 20s proteasome, the proteolytic core peptide within the 26s proteosome.

It has little or no activity against other protease classes.

Approved in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed myeloma who have received 1-3 prior lines of therapy.

Second generation proteasome inhibitor.

Belongs to the epoxiketone family and irreversibly binds the chemotrypsin like activity of the proteasome.

Targets the chemo trypsin like activity of the 20S proteasome.

More specific for the proteasome than bortezomib, which is a reversible proteosome inhibitor.

Has less reactivity against non-proteasomal proteases compared to bortezomib.

Has efficacy in patients refractory to bortezomib and at least one of the immune-mediated inflammatory disease agents.

Distinct mechanistically, more potent than bortezomib.

Proteasome inhibition occurs after 1 dose and is prolonged.

Peripheral neuropathy grade 2/3 occurs in less tha 1% of patients.

Fatigue dose limiting toxicity.

Side effects include fatigue, pancytopenia, dyspnea, diarrhea, and fever in up to 30% of patients who receive the drug.

Toxicity consists mainly of myelosuppression.

Pulmonary toxicities such as interstitial lung disease, pneumonitis, acute respiratory failure, pulmonary hypertension and hypertension have been reported.

Patients receiving carfilzomib experience cardiovascular adverse events, such as hypertension, heart failure, heart attacks, or arrhythmia.

Associated with more cardiac dysfunction then with bortezomib.

More than eight percent of patients experience high-grade cardiovascular adverse events.

Posterior reversible encephalopathy syndrome, TTP/HUS reported.

In a trial of 266 multiple myeloma patient with relapsed oral refractory disease received 20 mg meter squared on days one, 2, 8, 9, 15, and 16 every 28 days and then increase dose to 27 mg meter squared on the same schedule for up to 12 cycles: 0.4% had a CR, 4.7% at a very good partial response, and 19% and a partial response, for an overall response rate of 24%, an additional 12% had a minimal response yielding an overall clinical benefit of 36% and stable disease for at least 6 weeks was 32% (Siegel DSD et al).

In a phase 3 trial, overall response rate in pretreated, relapse refractory patients with multiple myeloma, overall response rates of 42-51% in bortezomib naïve patients, and 17% among patients who had previous bortezomib.

When combined with Lenalidomide and dexamethasone (CRd) the overall response rate in pretreated, relapse, and refractory patients with multiple myeloma is 78% with a complete or near completion response rate of 24%.

When combined with lenalidomide, and dexamethasone (CRd) in myeloma has a response rate of 100% in newly diagnosed patients, and a complete or near complete response rate of 61%.

Administered on 2 consecutive days, 1 week apart, in 28 day cycles.

Now 70 mg/m² weekly has been accepted dosage, and is associated with a hgher response rate then twice weekly administered drug.

Intravenous dosing of 20 mg/m2 concurrently with IV fluids and dexamethasone on initial treatment, and escalation to 27mg/m2 if first cycle tolerated well.

Responses are rapid in onset.

Dose limiting toxicity 70 mg/m2.

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