Usage
Antithymocyte Immunoglobulins (ATG) are prescribed for the prophylaxis and treatment of acute organ rejection in solid organ transplant recipients, primarily kidney transplants. They are also used in the treatment of aplastic anemia and graft-versus-host disease. These medications belong to the pharmacological class of immunosuppressants. ATG works by binding to and depleting T-lymphocytes, which are key mediators in the immune response responsible for organ rejection.
Alternate Names
Antithymocyte globulin (rabbit), Antithymocyte globulin (equine), ATG.
Brand names: Thymoglobulin®, ATGAM®
How It Works
Pharmacodynamics: ATG exerts its immunosuppressive effects by targeting and depleting T-lymphocytes. This depletion occurs through various mechanisms, including complement-mediated lysis, antibody-dependent cell-mediated cytotoxicity, and apoptosis (programmed cell death). The depletion of T-cells leads to a dampened immune response, preventing rejection of the transplanted organ.
Pharmacokinetics: ATG is administered intravenously. The drug exhibits variable absorption and distribution depending on the source (rabbit or horse). Metabolism and elimination pathways are not fully characterized, but it is presumed that the antibodies are broken down and cleared like endogenous immunoglobulins. It’s important to note that the pharmacokinetics of ATG can be impacted by patient-specific factors, such as the presence of pre-existing antibodies against the animal-derived proteins. Monitoring lymphocyte subsets is necessary because the CD4/CD8 ratio may be altered for up to a year following treatment.
Mode of Action: ATG binds to various T-cell surface antigens, including CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD45, and HLA-DR. This binding leads to the depletion of T-lymphocytes, thereby reducing the immune system’s ability to mount a rejection response. The intensity of immunosuppression with ATG is affected by several factors, including pre-existing antibodies to rabbit or equine antigens in the recipients.
Dosage
Standard Dosage
Adults:
- Kidney Transplant Prophylaxis: 1.5 mg/kg daily for 4-7 days, initiated prior to reperfusion of the donor kidney.
- Kidney Transplant Treatment (Acute Rejection): 1.5 mg/kg daily for 7-14 days.
Children: Pediatric dosing recommendations are often the same as for adults, but they should be carefully evaluated by a pediatric transplant specialist, considering factors like weight and age.
Special Cases:
- Elderly Patients: Same as adult dosing. Careful consideration and monitoring is recommended due to potential age-related decline in organ function.
- Patients with Renal Impairment: No dose adjustment necessary as per source materials, however extra monitoring is recommended.
- Patients with Hepatic Dysfunction: No dose adjustment necessary as per source materials, however extra monitoring is recommended.
- Obese Patients: The dosing should be based on ideal body weight rather than actual body weight.
Clinical Use Cases
Dosage recommendations are primarily related to transplantation. For other uses, consult specialized guidelines. It is crucial to note that the dosage of ATG can differ based on the source (rabbit or equine), underlying conditions, and co-administered medications. The dosage and duration of therapy must be individualized based on the patient’s clinical condition and response to treatment.
Dosage Adjustments
Dose reduction by 50% is recommended if the white blood cell (WBC) count falls between 2,000 and 3,000 cells/mm³ or the platelet count is between 50,000 and 75,000 cells/mm³. Discontinuation should be considered if WBC counts drop below 2,000 cells/mm³ or platelet counts fall below 50,000 cells/mm³.
Side Effects
Common Side Effects:
Fever, chills, leukopenia (low white blood cell count), thrombocytopenia (low platelet count), headache, nausea, vomiting, diarrhea, hypertension, and pain at the injection site.
Rare but Serious Side Effects:
Anaphylaxis (severe allergic reaction), cytokine release syndrome (CRS), serum sickness, infections (bacterial, fungal, viral, protozoal), and malignancies (lymphoma, lymphoproliferative disorders).
Long-Term Effects:
Increased risk of infections and certain cancers due to immunosuppression.
Adverse Drug Reactions (ADR):
Cytokine release syndrome, anaphylaxis, and serious infections require immediate medical intervention.
Contraindications
- History of allergy or anaphylaxis to rabbit or horse proteins.
- Active acute or chronic infections that would be exacerbated by further immunosuppression.
Drug Interactions
ATG can interact with other immunosuppressants, potentially leading to additive or synergistic effects and an increased risk of infections. Co-administration with live vaccines is contraindicated due to the risk of uncontrolled viral replication. Consult a comprehensive drug interaction database for a complete list of potential interactions. Interactions with specific drugs like etrasimod, everolimus, glatiramer should be avoided.
Pregnancy and Breastfeeding
Pregnancy: ATG is categorized as Pregnancy Category C. Its use during pregnancy should be restricted to situations where the potential benefit outweighs the risk to the fetus. Effective contraception is recommended for women of childbearing age during and for at least 3 months after treatment.
Breastfeeding: It is unknown if ATG is excreted in breast milk. However, as other immunoglobulins are excreted in human milk, breastfeeding should be discontinued during ATG therapy.
Drug Profile Summary
- Mechanism of Action: Depletion of T-lymphocytes through various mechanisms, leading to immunosuppression.
- Side Effects: Common: Fever, chills, leukopenia, thrombocytopenia, headache. Serious: Anaphylaxis, cytokine release syndrome, infections, malignancies.
- Contraindications: Hypersensitivity to rabbit or horse proteins, active serious infections.
- Drug Interactions: Other immunosuppressants, live vaccines.
- Pregnancy & Breastfeeding: Category C; breastfeeding contraindicated.
- Dosage: Variable depending on indication and patient factors; consult product information.
- Monitoring Parameters: WBC count, platelet count, lymphocyte subsets, signs of infection, and hypersensitivity reactions.
Popular Combinations
ATG is commonly used in combination with other immunosuppressants, like corticosteroids (e.g., methylprednisolone), calcineurin inhibitors (e.g., tacrolimus, cyclosporine), and antimetabolites (e.g., mycophenolate mofetil).
Precautions
- Pre-screening for allergies to rabbit or horse proteins is essential.
- Close monitoring for infections and other side effects is required.
- Prophylactic antimicrobial therapy may be considered.
- ATG should only be administered by physicians experienced in transplant medicine.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Antithymocyte immunoglobulins?
A: The dosage varies based on the indication (prophylaxis or treatment of rejection) and the specific ATG product used. For kidney transplant prophylaxis, the usual dose is 1.5 mg/kg/day for 4-7 days. For treatment of acute rejection, 1.5 mg/kg/day for 7-14 days is common.
Q2: What are the common side effects of ATG?
A: Common side effects include fever, chills, leukopenia, thrombocytopenia, headache, nausea, and injection site reactions.
Q3: What are the serious side effects of ATG?
A: Serious side effects include anaphylaxis, cytokine release syndrome, serum sickness, infections, and increased risk of certain cancers.
Q4: What are the contraindications to using ATG?
A: Contraindications include a history of hypersensitivity to rabbit or horse proteins and active serious infections.
Q5: Can ATG be used in pregnant or breastfeeding women?
A: ATG is a Pregnancy Category C drug and should only be used if the potential benefit outweighs the risk to the fetus. Breastfeeding should be discontinued during ATG therapy.
Q6: How is ATG administered?
A: ATG is administered as an intravenous infusion. Premedication with corticosteroids and antihistamines is recommended. Close patient monitoring during and after infusion is necessary.
Q7: What are the key monitoring parameters during ATG therapy?
A: Monitor complete blood counts (including WBC and platelet counts), lymphocyte subsets, and watch for signs of infection and hypersensitivity reactions.
Q8: How does ATG interact with other immunosuppressants?
A: ATG can have additive or synergistic effects with other immunosuppressants, which may increase the risk of infections and other adverse events. The dosage of concomitant immunosuppressants may need to be adjusted.
Q9: What is cytokine release syndrome (CRS), and how is it managed?
A: CRS is a systemic inflammatory response that can occur after ATG infusion. Symptoms can range from mild (fever, chills) to severe (hypotension, respiratory distress). Management involves supportive care and, in severe cases, immunomodulatory therapies.
Q10: How can the risk of infections be minimized during ATG therapy?
A: Prophylactic antimicrobial therapy may be considered based on the patient’s risk factors. Strict adherence to infection control measures, such as hand hygiene and avoiding contact with sick individuals, is also crucial. Patients should be educated about the signs and symptoms of infection and instructed to report them promptly.
