KARPILRED

Indications

• Multiple myeloma

Dosage

Children: Paediatric dosing information is not available; refer to BNF for Children for guidance.

Adults: The dosing regimen for adults should be determined by a specialist, and it is advised to consult product literature or local protocols for specific dosing information.

Mechanism of action

Carfilzomib irreversibly and selectively binds to the N-terminal threonine-containing active sites of the 20S proteasome, particularly inhibiting the chymotrypsin-like site, which is crucial for protein degradation. This inhibition leads to cell cycle arrest and apoptosis of cancerous cells, resulting in decreased cellular proliferation.

Pharmacodynamics

Following intravenous administration, carfilzomib exhibits suppression of proteasome chymotrypsin-like activity, achieving inhibition levels of 79% to 89% in peripheral blood mononuclear cells within 1 hour after the first dose at 15 mg/m2. The effects persist for at least 48 hours post dosing, with additional inhibition observed in immunoproteasome subunits. Resistance may develop, possibly due to the up-regulation of P-glycoprotein, and it has shown to be more potent than bortezomib.

Pharmacokinetics

Carfilzomib is rapidly absorbed following intravenous administration, with a volume of distribution that indicates extensive tissue distribution. It is primarily eliminated via the liver, and undergoes metabolic processes that yield inactive metabolites. The half-life is approximately 15 minutes post-infusion, with drug levels decreasing rapidly after administration.

Contra-indications

• Hypersensitivity to carfilzomib or any of its components
• Severe cardiac disorders
• Active hepatitis B infection

Adverse effects

• Anaemia
• Injection site reactions
• Fatigue
• Hypertension
• Heart failure
• Cardiac arrest
• Myocardial infarction
• Pulmonary hypertension
• Neutropenia
• Thrombocytopenia
• Progressive multifocal leukoencephalopathy (PML)
• Hepatitis B reactivation
• Gastrointestinal perforation
• Clostridium difficile colitis

Interactions

• Combined hormonal contraceptives (may decrease efficacy)
• Antiviral therapies (consider for patients with positive hepatitis B serology)
• Other proteasome inhibitors

Precautions

• Monitor for signs of infusion-related reactions
• Monitor cardiac function due to risk of cardiac events
• Screen for hepatitis B before initiation
• Use caution in patients with renal impairment
• Consider dose adjustment in patients with hepatic impairment

Pregnancy

Carfilzomib is not recommended during pregnancy due to potential harm to the fetus. Effective contraception is advised during treatment.

Breast-feeding

It is not known whether carfilzomib is excreted in human milk. A decision should be made to discontinue breastfeeding or to discontinue the drug, considering the importance of the drug to the mother.

Storage

Store in a refrigerator (2°C to 8°C). Do not freeze. Protect from light.

Formulations

• Solution for injection (available in various concentrations)

Mechanism of action

Carfilzomib is made up of four modified peptides and acts as a proteasome inhibitor. Carfilzomib irreversibly and selectively binds to N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. This 20S core has 3 catalytic active sites: the chymotrypsin, trypsin, and caspase-like sites. Inhibition of the chymotrypsin-like site by carfilzomib (β5 and β5i subunits) is the most effective target in decreasing cellular proliferation, ultimately resulting in cell cycle arrest and apoptosis of cancerous cells. At higher doses, carfilzomib will inhibit the trypsin-and capase-like sites.

Pharmacodynamics

Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like activity when measured in blood 1 hour after the first dose. On Day 1 of Cycle 1, proteasome inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 89% at 15 mg/m2, and from 82% to 83% at 20 mg/m2. In addition, carfilzomib administration resulted in inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging from 26% to 32% and 41% to 49%, respectively, at 20 mg/m2. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing. Resistance against carfilzomib has been observed and although the mechanism has not been confirmed, it is thought that up-regulation of P-glycoprotein may be a contributing factor. Furthermore, studies suggest that carfilzomib is more potent than bortezomib.