Thymoglobulin (Anti-Thymocyte Globulin - Rabbit): Pharmacologic Overview
Class: Polyclonal T-cell–depleting immunoglobulin
Indication: Prophylaxis and treatment of acute rejection in kidney transplantation (U.S. label), widely used off-label for induction in high immunologic risk patients and in steroid-resistant rejection.
Mechanism of Action
Thymoglobulin is a polyclonal IgG antibody preparation derived from rabbits immunized with human thymocytes. It contains antibodies against multiple T-cell surface antigens (CD2, CD3, CD4, CD8, CD11a, CD18, HLA-DR, CD28, β2-microglobulin), resulting in:
- Complement-mediated T-cell lysis
- Opsonization-induced phagocytosis
- Apoptosis of T cells
- Modulation of adhesion and trafficking molecules
- Upregulation of T-regulatory cells & immunomodulation
Profound T-cell depletion occurs within 24 hours and may persist weeks to months.
Clinical Use Overview
| Setting | Typical Dose | Duration | Notes |
|---|---|---|---|
| Induction in kidney transplant | 1–1.5 mg/kg/day IV | 3–7 days | Administer before graft reperfusion |
| Treatment of acute rejection | 1.5 mg/kg/day IV | 7–14 days | Steroid-resistant cellular rejection |
| Off-label (U.S. centers) | Aplastic anemia, GVHD prophylaxis | Variable | Hematology/oncology protocols |
Dosing per U.S. label: 1.5 mg/kg/day x 4–7 days (prophylaxis) or 7–14 days (treatment)
Antithymocyte globulin (ATG) induction
Antithymocyte globulin (ATG) induction refers to the use of T-cell–depleting immunoglobulin therapy—most commonly Thymoglobulin (rabbit ATG)—administered at the time of organ transplantation to profoundly suppress the recipient’s immune system and prevent early acute rejection.
Purpose of ATG Induction
ATG induction therapy is designed to achieve rapid, profound, but temporary depletion of circulating T lymphocytes during the peri-transplant period, when alloimmune activation against the new organ is most intense.
- It provides immediate immunosuppression before maintenance drugs (calcineurin inhibitors, mycophenolate, prednisone) can reach full effect.
- It is used both in standard immunologic risk and especially in high immunologic risk recipients (e.g., repeat transplant, sensitized patients, African American recipients, presence of donor-specific antibodies).
Preparation Guide
Reconstitution
- Each vial: 25 mg lyophilized powder.
- Reconstitute with 5 mL Sterile Water for Injection (SWFI).
- Concentration: 5 mg/mL.
- Gently invert—do NOT shake.
Dilution
- Dilute dose in 0.9% NaCl or D5W to 50–500 mL total volume.
- Use 0.22 micron filter inline.
- Infusion time:
- First dose ≥ 6 hours, subsequent doses ≥ 4 hours.
Peripheral IV Administration Precaution
- If given peripherally, MUST add to infusion:
- Heparin 1,000 units + Hydrocortisone 50 mg in 0.9% NaCl (not D5W – precipitation risk)
- Use central line if possible.
Beyond Use Date (BUD)
| Preparation Stage | Storage Condition | Maximum BUD | Key Comments |
|---|---|---|---|
| Reconstituted vial (not yet diluted) | 2–8 °C | 24 h | Protect from light; single-use only |
| Diluted in 0.9% NaCl IV solution | Room temperature or 2–8 °C | 24 h | Includes infusion time; discard remainder |
Compatibility/Incompatibility Data
Thymoglobulin is a highly proteinaceous biologic sensitive to pH, ionic strength, and the carbohydrate content of the diluent. Proper diluent selection is critical for preventing precipitation and maintaining product integrity during infusion.
Preferred Diluent and Compatible Solutions
- Compatible Diluent: 0.9% Sodium Chloride Injection (Normal Saline) – the only manufacturer-recommended and validated diluent.
- Final Concentration: Do not exceed 0.5 mg/mL after dilution in 0.9% NaCl.
- Rationale: Saline maintains neutral pH and isotonicity, preserving protein structure and preventing aggregation.
Incompatibility with Dextrose-Containing Solutions (D5W)
- Thymoglobulin is incompatible with dextrose-containing solutions (e.g. D5W).
- Precipitation occurs, especially when mixed with heparin and hydrocortisone.
- Mechanism: Carbohydrate interaction and loss of ionic balance disrupt electrostatic stability, causing protein aggregation.
- Practice Rule: Do not substitute D5W as a diluent or co-infuse with Thymoglobulin.
Co-Administration and IV Line Use
- Y-site compatibility: No supporting data; manufacturer advises against mixing with other drugs in the same line.
- Best Practice: Use a dedicated IV line for Thymoglobulin, or flush thoroughly with saline before and after if shared access is unavoidable.
- Filter Requirement: Administer through a 0.22 µm in-line filter to remove microaggregates.
Physical and Chemical Stability
| Diluent | Compatibility | Precipitation Risk | Notes |
|---|---|---|---|
| 0.9% Sodium Chloride | Compatible | Low | Preferred diluent; maintains protein stability |
| D5W (5% Dextrose) | Incompatible | High | Causes precipitation, especially with heparin/hydrocortisone |
| Ringer’s Lactate | Not evaluated | Unknown | Possible calcium–protein interaction risk |
| Plasma-Lyte or mixed electrolytes | Limited data | Not recommended | Ionic imbalance may destabilize biologic |
Clinical and Safety Implications
Saline is the clinically preferred diluent due to its stability and compatibility with biologic proteins. Dextrose-based solutions increase precipitation risk, reduce potency, and may lead to embolic risk from protein aggregates.
Key Professional Takeaways
- Always dilute Thymoglobulin in 0.9% NaCl only.
- Do not use D5W – high precipitation and instability risk.
- Use a 0.22 µm in-line filter for all infusions.
- Do not mix with other drugs in the same IV line.
- Use within 24 hours of compounding (even if refrigerated).
Premedication
30–60 min prior to each dose:
| Medication | Rationale |
|---|---|
| Acetaminophen | Prevent fever/chills |
| Diphenhydramine | Reduce histamine-mediated reactions |
| Methylprednisolone | Prevent cytokine release syndrome (CRS) |
Supportive Therapy
Prophylaxis
| Class | Agent Examples |
|---|---|
| Antiviral | Valganciclovir (CMV risk) |
| Antifungal | Fluconazole |
| PJP prophylaxis | TMP–SMX |
Infusion Reactions & CRS
High-risk during first 1–2 doses due to cytokine release.
Symptoms: fever, chills, hypotension, dyspnea, tachycardia, ARDS, chest pain
Management:
- Slow infusion rate.
- Additional steroids + antihistamines PRN.
- For anaphylaxis: stop infusion + epinephrine 0.3–0.5 mL SC (1:1000).
Adverse Effects
| Adverse Effect | Incidence |
|---|---|
| Fever / chills | 46–63% |
| Leukopenia | 57–63% |
| Thrombocytopenia | 10–36% |
| Hypertension | 18–37% |
| Infection (overall) | 56–76% |
| CMV infection | Up to 12–18% |
| Serum sickness (day 5–15) | 1–5% |
| Malignancy risk | PTLD cases reported |
| Anaphylaxis | Rare but fatal cases reported |
Monitoring Parameters
| Parameter | Frequency |
|---|---|
| CBC with diff, platelets | Daily |
| Vital signs during infusion | q15–30 min |
| CMP, K⁺, Mg²⁺ | Daily |
| CMV PCR, EBV load | Weekly (if high risk) |
| T-cell counts (CD3) | Optional for redosing |
| Signs of serum sickness | Day 5–15 |
Hold or reduce dose if:
- WBC 2,000–3,000 → give ½ dose
- WBC <2,000 or Plt <50,000 → HOLD therapy
Professional Clinical Pearls
- Avoid mixing in dextrose if giving heparin/hydrocortisone
- Start infusion BEFORE reperfusion to reduce delayed graft function
- Consider lower steroid exposure protocols with ATG induction
- Not effective for antibody-mediated rejection (AMR)—use plasmapheresis + IVIG
- Serum sickness risk increases with retreatment—watch for fever/arthralgia
- Use CMV prophylaxis in D+/R− transplants
- Thymoglobulin provides broad and powerful immunosuppression but requires meticulous infection control and hematologic monitoring.
- Dosing must be product-specific, as potency differs among ATG formulations (rabbit vs equine).
- Premedication, slow infusion, and vigilant supportive care are essential to minimize adverse events and optimize graft outcomes.
References
- U.S. Food and Drug Administration. Thymoglobulin (Anti-thymocyte Globulin [Rabbit]) Package Insert. Revised 2024. Accessed October 26, 2025. https://www.fda.gov/media/74641/download
- Sanofi-Aventis Canada Inc. Thymoglobulin (Anti-thymocyte Globulin [Rabbit]) Product Monograph. Toronto, ON: Sanofi-Aventis Canada Inc.; Revised March 7, 2016. Accessed October 26, 2025. https://www.sanofi.com/assets/countries/canada/docs/products/prescription-products/thymoglobulin-en.pdf
- Noël C, Abramowicz D, Durand D, et al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. Nephrol Dial Transplant. 2017;32(10):1601-1609. https://academic.oup.com/ndt/article/32/10/1601/2374143
- Gaber AO, Knight RJ, Patel SJ, et al. Rabbit antithymocyte globulin induction versus no induction in renal transplantation: three-year follow-up of the Thymoglobulin Induction Study Group trial. PLoS One. 2016;11(1):e0146238. https://pmc.ncbi.nlm.nih.gov/articles/PMC4689936/
- Sanofi Genzyme. Thymoglobulin: Efficacy and Safety Data. Accessed October 26, 2025. https://www.thymoglobulin.com/efficacy-safety-data
- Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355(19):1967-1977. https://pubmed.ncbi.nlm.nih.gov/28376289/
- Sanofi Genzyme. Thymoglobulin: Dosing and Administration Guide. Accessed October 26, 2025. https://www.thymoglobulin.com/dosing