Daclizumab

Usage

Daclizumab was previously indicated as an immunosuppressive agent. It had two distinct formulations and uses:

1. Zenapax (daclizumab injection): Approved as an adjunct treatment for the prophylaxis of acute organ rejection in patients receiving renal transplants. It was generally used in combination with other immunosuppressants like cyclosporine and corticosteroids.

2. Zinbryta (daclizumab injection): Approved for the treatment of relapsing forms of multiple sclerosis (MS) in adult patients who had an inadequate response to two or more MS drugs.

Pharmacological Classification: Immunosuppressant, monoclonal antibody (specifically, an interleukin-2 receptor blocking antibody).

Mechanism of Action: Daclizumab binds to the alpha subunit (CD25) of the interleukin-2 (IL-2) receptor on activated T-lymphocytes. This binding prevents IL-2-mediated activation and proliferation of these cells, which play a critical role in the immune response, hence suppressing the immune reaction involved in organ rejection or MS relapse.

Alternate Names

• Daclizumab beta (previous INN)

Brand Names:

• Zenapax (discontinued)
• Zinbryta (discontinued)

How It Works

Pharmacodynamics: Daclizumab primarily affects activated T cells by binding to the IL-2 receptor, thereby suppressing the immune response. This reduces the risk of organ rejection in transplant patients and the frequency of MS relapses.

Pharmacokinetics:

• Absorption: Zenapax: After intravenous administration, peak serum concentration is achieved rapidly. Zinbryta: Following subcutaneous administration, bioavailability is high.
• Metabolism: Daclizumab is not extensively metabolized by CYP enzymes. Being a monoclonal antibody, its breakdown is expected to follow general protein catabolism pathways.
• Elimination: Primarily via protein catabolism, not through specific renal or hepatic pathways. The half-life varies, but is relatively long (around 20-30 days).

Mode of Action: Daclizumab is a humanized monoclonal antibody that specifically targets the CD25 subunit of the high-affinity IL-2 receptor expressed on activated T cells. IL-2 is crucial for the proliferation and differentiation of T cells. By blocking the IL-2 receptor, daclizumab inhibits IL-2 binding and subsequent signaling, leading to the suppression of T cell activation and proliferation.

Receptor Binding: Daclizumab specifically binds to the IL-2 receptor alpha chain (CD25).

Elimination pathways: Daclizumab, being a large molecule, is predominantly eliminated through proteolytic degradation, a general protein catabolism process, rather than specific hepatic or renal pathways.

Dosage

Note: Daclizumab (both Zenapax and Zinbryta) has been withdrawn from the market due to safety concerns, particularly the risk of serious liver injury and other immune-mediated disorders. The information below is for historical reference only and should not be used for current clinical practice.

Standard Dosage (when it was marketed):

Adults (Zenapax):

• 1.0 mg/kg IV infusion over 15 minutes.
• The first dose was administered within 24 hours before transplantation.
• Four subsequent doses were administered at 14-day intervals.

Adults (Zinbryta):

• 150 mg subcutaneous injection once monthly.

Children: Zenapax: 1.0 mg/kg IV infusion. Zinbryta: Not recommended for use in children under 18.

Special Cases:

• Elderly Patients: Use with caution; limited clinical data are available.
• Patients with Renal Impairment: No dose adjustment necessary for Zenapax.
• Patients with Hepatic Dysfunction: Zenapax: No data available. Zinbryta: Contraindicated.
• Patients with Comorbid Conditions: Use with caution in patients with other autoimmune diseases or pre-existing infections.

Clinical Use Cases (when it was marketed):

Daclizumab (Zenapax) was specifically indicated for kidney transplant rejection prophylaxis and had no other clinical use cases listed in the provided information.

Dosage Adjustments (when it was marketed):

No formal dosage adjustments were routinely made except for cases of hepatic dysfunction (Zinbryta) where it was contraindicated.

Side Effects

Common Side Effects:

• Nausea, vomiting, diarrhea, constipation
• Headache, dizziness, tremor
• Upper respiratory tract infection, influenza
• Rash, itching, skin reactions
• Injection site reaction (Zinbryta)

Rare but Serious Side Effects:

• Liver injury (including autoimmune hepatitis and liver failure) – This was a significant concern leading to the drug’s withdrawal.
• Immune-mediated disorders (skin reactions, lymphadenopathy, colitis)
• Severe infections
• Allergic reactions, anaphylaxis
• Depression and suicidal ideation

Long-Term Effects:

The long-term safety profile of daclizumab could not be fully established due to its withdrawal from the market. However, prolonged immunosuppression carries the risk of increased susceptibility to infections and malignancies.

Adverse Drug Reactions (ADR): Serious liver injury and other immune-mediated disorders were the most significant ADRs.

Contraindications

• Known hypersensitivity to daclizumab or any of its components.
• Pre-existing liver disease or hepatic impairment (Zinbryta).
• Severe active infections.

Drug Interactions

Daclizumab may interact with other immunosuppressants, hepatotoxic drugs, and live vaccines. It is important to inform the doctor about all concomitant medications, including over-the-counter drugs and supplements. Specifically:

• Concomitant use of hepatotoxic drugs: Increased risk of hepatic injury.
• Live Vaccines: Not recommended during treatment with daclizumab due to the risk of infection.
• CYP450 Interactions: No significant CYP450 interactions have been reported.

Pregnancy and Breastfeeding

Pregnancy Safety Category: C (old classification; the current system doesn’t assign letters).

Fetal Risks: Animal studies have shown increased risk of fetal loss at high doses. Human data are limited, and daclizumab should be avoided during pregnancy unless the potential benefit outweighs the potential risk.

Breastfeeding: It is unknown if daclizumab passes into breast milk. Due to potential risks to the infant, breastfeeding is generally not recommended while taking daclizumab.

Drug Profile Summary

Note: The following is a historical summary due to the drug’s market withdrawal.

• Mechanism of Action: IL-2 receptor blocking antibody, suppresses immune responses by inhibiting T-cell activation.
• Side Effects: Liver damage, immune-mediated disorders, infections, rash, injection site reactions, nausea, headache.
• Contraindications: Hypersensitivity, pre-existing liver disease (Zinbryta).
• Drug Interactions: Immunosuppressants, hepatotoxic drugs, live vaccines.
• Pregnancy & Breastfeeding: Avoid unless absolutely necessary.
• Dosage: Zenapax: 1mg/kg IV every 14 days for 5 doses. Zinbryta: 150 mg SC monthly.
• Monitoring Parameters: Liver function tests (ALT, AST, bilirubin), complete blood count, signs of infection.

Popular Combinations (Historically)

• Zenapax was often used in combination with cyclosporine and corticosteroids in renal transplant recipients.

Precautions

• Close monitoring for liver injury and immune-mediated reactions.
• Careful assessment of infection risk.
• Contraception counseling for women of childbearing potential.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Daclizumab?

A: Daclizumab is no longer on the market. The recommended dose for Zenapax was 1 mg/kg IV every 14 days for five doses. For Zinbryta, the recommended dose was 150 mg subcutaneously once monthly.

Q2: What are the serious side effects of Daclizumab?

A: The most serious side effects were liver damage (including autoimmune hepatitis and liver failure), immune-mediated disorders (affecting skin, lymph nodes, and gut), and severe infections. These risks led to the drug’s withdrawal.

Q3: Can Daclizumab be used during pregnancy?

A: Daclizumab should be avoided during pregnancy due to the potential for fetal harm observed in animal studies. If the potential benefit justifies the potential risk, close monitoring is essential.

Q4: How does Daclizumab work?

A: Daclizumab is a monoclonal antibody that blocks the IL-2 receptor on activated T cells, suppressing the immune response.

Q5: Why was Daclizumab withdrawn from the market?

A: Daclizumab was withdrawn due to reports of serious liver injury, including some fatal cases of autoimmune hepatitis.

Q6: What are the alternative treatments for the conditions Daclizumab was used for?

A: Several other immunosuppressants and disease-modifying therapies are available for organ transplantation and multiple sclerosis. The choice of treatment depends on individual patient factors and should be determined by a specialist.

Q7: Is there any specific monitoring needed for patients taking Daclizumab?

A: (Historically) Regular liver function tests (ALT, AST, bilirubin) were crucial for patients taking Daclizumab, along with monitoring for signs of infection and other immune-mediated disorders.

Q8: Can Daclizumab be used in children?

A: Zinbryta was not approved for use in children under 18. Zenapax had an approved pediatric dose, but it’s no longer marketed.

Q9: What should I do if my patient experiences side effects while taking Daclizumab?

A: Since Daclizumab is not available, this question is no longer relevant. However, if a patient experienced side effects while taking any medication, appropriate medical evaluation and management are needed. This may include stopping the medication, supportive care, or specific treatment for the side effect. Consulting with a specialist might be necessary.