Carfilzomib

Usage

Carfilzomib is prescribed for the treatment of relapsed or refractory multiple myeloma (a type of bone marrow cancer) in patients who have received one or more previous treatments. It is a proteasome inhibitor, an antineoplastic agent. Carfilzomib works by blocking the action of proteasomes, which are cellular complexes responsible for breaking down proteins. By inhibiting proteasomes in myeloma cells, carfilzomib disrupts cellular processes, leading to cell death.

Alternate Names

Carfilzomib is also known by its brand name, Kyprolis.

How It Works

Pharmacodynamics: Carfilzomib irreversibly inhibits the chymotrypsin-like activity of the 20S proteasome, a component responsible for protein degradation within cells. This leads to an accumulation of proteins, disrupting vital cellular functions and inducing apoptosis (programmed cell death) in myeloma cells.

Pharmacokinetics:

• Absorption: Administered intravenously.
• Metabolism: Primarily metabolized by epoxide hydrolases and, to a lesser extent, by CYP3A4.
• Elimination: Primarily eliminated via hepatic metabolism and biliary excretion. Renal excretion plays a minor role.

Mode of Action: Carfilzomib irreversibly binds to the N-terminal threonine residue of the chymotrypsin-like β5 subunit of the 20S proteasome. This binding inhibits the proteasome’s ability to degrade ubiquitinated proteins, leading to cellular stress and apoptosis in myeloma cells.

Receptor binding, enzyme inhibition, or neurotransmitter modulation: Carfilzomib acts through enzyme inhibition (proteasome inhibition).

Dosage

Standard Dosage

Adults: Carfilzomib is administered intravenously. Various dosage regimens exist depending on the specific combination therapy. For example, in combination with dexamethasone, one regimen involves administering carfilzomib at 20 mg/m² on days 1 and 2 of cycle 1, escalating to 56 mg/m² on days 8, 9, 15, and 16, and continuing at 56 mg/m² twice weekly in subsequent cycles. Another regimen, in combination with daratumumab and dexamethasone administered once weekly, uses a starting dose of 20 mg/m² in cycle 1, escalating to 70 mg/m² on days 8 and 15. Consult the full prescribing information for all dosing regimens, including specific schedules, cycle durations, and dose modifications based on the specific combination.

Children: The safety and efficacy of carfilzomib in children have not been established.

Special Cases:

• Elderly Patients: Higher incidence of certain adverse effects, including cardiac events. Dose adjustments may be necessary, particularly for those over 75 years of age.
• Patients with Renal Impairment: No initial dose adjustment required, administer after dialysis if applicable.
• Patients with Hepatic Dysfunction: Higher incidence of adverse events and hepatic abnormalities. Liver enzymes and bilirubin should be monitored, and dose modifications made as needed.
• Patients with Comorbid Conditions: Close monitoring is required, especially for patients with pre-existing cardiac conditions, pulmonary hypertension, or renal impairment.

Clinical Use Cases

Carfilzomib is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary indication is for the treatment of multiple myeloma.

Dosage Adjustments

Dose reductions are based on toxicity and may be required in cases of cardiac events, pulmonary complications, hepatic dysfunction, or other significant adverse effects. Specific dose reduction guidelines are provided in the full prescribing information.

Side Effects

Common Side Effects:

Anemia, fatigue, diarrhea, high blood pressure, fever, upper respiratory tract infections, low platelets, cough, dyspnea, insomnia.

Rare but Serious Side Effects:

Cardiac events (heart failure, ischemia, arrhythmias), pulmonary hypertension, tumor lysis syndrome, acute kidney injury, severe thrombocytopenia, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, infusion reactions, PRES (posterior reversible encephalopathy syndrome).

Long-Term Effects:

Potential long-term effects include cardiac dysfunction and renal impairment. Regular monitoring of cardiac and renal function is recommended.

Adverse Drug Reactions (ADR):

Clinically significant ADRs include severe cardiac events, acute kidney injury, tumor lysis syndrome, thrombotic microangiopathy, and severe infusion reactions. These require immediate medical intervention.

Contraindications

Hypersensitivity to carfilzomib, breastfeeding. Refer to prescribing information for concomitant medications for additional contraindications.

Drug Interactions

Carfilzomib interacts with numerous medications, including strong CYP3A4 inhibitors and inducers. Consult a comprehensive drug interaction resource for a complete list. Notable interactions include:

• CYP450 interactions: Carfilzomib is partly metabolized by CYP3A4.
• Commonly prescribed medications: Interactions with dexamethasone, lenalidomide, daratumumab, and other medications used in multiple myeloma treatment regimens.
• OTC drugs and supplements: Co-administration with certain supplements, like St. John’s Wort, may alter carfilzomib levels.

Pregnancy and Breastfeeding

Carfilzomib is contraindicated during pregnancy and breastfeeding. It can cause fetal harm. Females of reproductive potential should use effective contraception during and for 6 months after treatment. Males with female partners of reproductive potential should use effective contraception during and for 3 months after treatment. Breastfeeding should be avoided during and for 2 weeks following the last dose of carfilzomib.

Drug Profile Summary

• Mechanism of Action: Proteasome inhibitor.
• Side Effects: Anemia, fatigue, diarrhea, high blood pressure, cardiac events, pulmonary complications, renal impairment.
• Contraindications: Hypersensitivity, pregnancy, breastfeeding.
• Drug Interactions: Multiple drug interactions, consult comprehensive resources.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: Variable, consult prescribing information for specific regimens.
• Monitoring Parameters: Cardiac function (ECG, echocardiogram), renal function (serum creatinine, eGFR), blood counts (CBC with differential), liver function tests (LFTs), electrolytes.

Popular Combinations

Carfilzomib is commonly used in combination with dexamethasone, lenalidomide, and daratumumab, as well as other agents for treating multiple myeloma. These combinations are used to enhance efficacy and potentially overcome drug resistance.

Precautions

• General Precautions: Assess cardiac, renal, and hepatic function prior to and during treatment. Monitor for signs of adverse reactions.
• Specific Populations:
  • Pregnant Women: Contraindicated.
  • Breastfeeding Mothers: Contraindicated.
  • Children & Elderly: Safety and efficacy not established in children. Increased risk of adverse effects in the elderly.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Carfilzomib?

A: Carfilzomib dosage varies depending on the combination regimen and cycle. Consult the full prescribing information for specific regimens.

Q2: What are the most common side effects of Carfilzomib?

A: Common side effects include anemia, fatigue, diarrhea, high blood pressure, and respiratory tract infections.

Q3: What are the serious side effects of Carfilzomib?

A: Serious side effects include cardiac events (e.g., heart failure), pulmonary complications, tumor lysis syndrome, renal impairment, and thrombotic microangiopathy.

Q4: Can Carfilzomib be used in patients with renal impairment?

A: No initial dose adjustment is needed for patients with renal impairment. If the patient is on dialysis, administer carfilzomib after dialysis.

Q5: Is Carfilzomib safe to use during pregnancy?

A: No. Carfilzomib is contraindicated during pregnancy and can cause fetal harm.

Q6: Can Carfilzomib be used during breastfeeding?

A: No. Carfilzomib is contraindicated during breastfeeding. Mothers should discontinue breastfeeding during treatment and for two weeks after the final dose.

Q7: What are the key drug interactions with Carfilzomib?

A: Carfilzomib interacts with many medications, including strong CYP3A4 inhibitors and inducers. Consult a comprehensive resource for a complete list.

Q8: How is Carfilzomib administered?

A: Carfilzomib is administered intravenously. The duration of infusion depends on the specific dose and regimen.

Q9: What monitoring parameters are essential for patients receiving Carfilzomib?

A: Monitor cardiac function (ECG, echocardiogram), renal function (serum creatinine, eGFR), blood counts (CBC with differential), liver function tests (LFTs), and electrolytes.

Q10: What is the mechanism of action of Carfilzomib?

A: Carfilzomib is a proteasome inhibitor, targeting the chymotrypsin-like activity of the 20S proteasome. This disrupts essential cellular processes and leads to apoptosis in myeloma cells.