Belatacept for Prophylaxis in Kidney Transplantation

Overview:

Belatacept, a potent immunosuppressive agent, has emerged as a promising alternative for prophylaxis given for kidney transplantation. Unlike traditional calcineurin inhibitors such as Tacrolimus and Cyclosporine, Belatacept selectively inhibits T-cell activation by blocking the CD28-CD80/86 costimulatory pathway. By preventing this important step in the immune response cascade, Belatacept offers a unique mechanism of action that reduces the risk of chronic nephrotoxicity and improves long-term graft survival, which is the ultimate goal of organ transplantation. In 2011, this costimulation blocker was approved by the United States Food and Drug Administration (USFDA) for kidney transplant individuals.

Dosage and Route of Administration:

Belatacept should be administered through an intravenous route, and this drug should always be administered with Basiliximab, Mycophenolate mofetil, and corticosteroids. The dose necessary for a particular individual depends on the body weight. This assessment should be done before the initiation of treatment and should not be changed during treatment. The dose should be altered only when there is a difference in the weight of more than 10 percent.

Dosing for Initial Phase:

An initial dose of 10 mg (milligrams) is given on day one after transplantation, day five, end of second, fourth, eighth, and twelfth week after transplantation.

Dosing for Maintenance Phase:

At the end of the 16th week and every four weeks thereafter, a maintenance dose of 5 mg (milligrams) of Belatacept is given.

For Patients:

What Is Kidney Transplantation?

Kidney transplantation is a surgical procedure done for individuals with renal (kidney) failure or chronic kidney disease without response to dialysis. This procedure replaces the diseased or non-functional kidneys with healthier ones. The kidney damage can occur as a result of chronic comorbidities like diabetes mellitus (high blood glucose levels), hypertension (elevated blood pressure), or other genetic disorders. Kidney transplantation is done only when the compatibility between the donor and the receiver is completely matched. The main objectives for transplanting a kidney are to improve the quality of performance of the kidneys and to avoid the need for ongoing dialysis.

What Is Prophylaxis After Kidney Transplantation?

Prophylaxis after a kidney or organ transplantation is necessary to prevent any complications arising from the presence of a donor organ in the body. This is done to avoid the rejection of the received organ by the body. Prophylactic measures involve the use of immunosuppressive medications to suppress the recipient's immune response by the immune system, preventing it from attacking and rejecting the transplanted kidney. Additionally, prophylaxis may include antibiotics to prevent attack by infectious agents, antiviral regimens to prevent viral reactivation, and other supportive therapies to maintain the health of the transplanted organ. Prophylactic measures also make sure that the prognosis of kidney transplantation is favorable.

Why Is Belatacept Given as a Prophylactic Drug After Kidney Transplantation?

A common complication that arises as a result of kidney transplantation is the rejection of the received organ. This occurs due to the activity of T lymphocytes in the body. This is because the received organ is considered a foreign object by the body, and the body tries to eliminate this foreign body by activating a T cell response in the body. These activated T cells can infiltrate the transplanted kidney and cause damage by initiating an immune-mediated attack, leading to rejection.

To stop this process and prevent rejection, Belatacept is given as a prophylactic drug. Belatacept helps prevent rejection by selectively inhibiting the activation of T cells. It works by blocking the co-stimulatory signal that is required for full activation of T cells. By interfering with this signal, Belatacept prevents the T cells from becoming fully activated and mounting an aggressive immune response against the transplanted kidney. This helps to dampen the immune response and reduce the risk of rejection without directly suppressing the entire immune system, as some traditional immunosuppressive medications do. As a result, Belatacept can help maintain the function and longevity of the transplanted kidney.

How Is Belatacept Taken?

Belatacept is an intravenously (through vein) administered drug that is given right after transplantation and at scheduled intervals. The calculated dosage will be administered only by a medical professional.

What Are the Side Effects of Taking Belatacept?

• As Belatacept suppresses the immune activity in the body, patients under this drug after kidney transplantation are highly prone to developing infections. This includes attacks by bacterial, viral, and fungal infectious agents. The most common infections seen are Cytomegalovirus infection, Epstein-Barr virus, tuberculosis (bacterial infection), Herpes infection, mumps, measles, and rubella.

• Sometimes, some viral attacks can cause damage to the received kidney. Examples of such kinds of nephropathy are JC (John Cunningham) virus-associated nephropathy and polyomavirus-associated nephropathy.

• The attack by the JC virus can also cause damage to cranial structures, leading to progressive multifocal leukoencephalopathy. This can cause motor dysfunction and disability in people.

• There is a chance that the kidney received will be rejected by the host body (graft rejection). In some people, the received kidney may function poorly.

• There can be abundant growth of lymphocytes in the body. This increases the risk of developing lymphomas and lymphoproliferative disorder. Belatacept works by suppressing the immune system to inhibit elimination of the received or transplanted organ, but this suppression also increases the risk of post-transplant lymphoproliferative disorder by allowing unchecked proliferation of Epstein-Barr virus (EBV)-infected B lymphocytes, which is a known risk factor for lymphoproliferative disorder after transplantation.

• Some kinds of malignancies are also noted after transplantation and Belatacept use. For example, non-melanoma skin cancer is a common occurrence in such individuals. Cyclosporine is given along with Belatacept to treat this condition.

• Some people develop diabetes mellitus (new-onset diabetes mellitus after transplantation). This is generally seen in people after one year of taking Belatacept.

Other Side Effects Associated With Belatacept Use Are:

• Headaches.

• Nausea.

• Cognitive decline.

• Sleeping difficulties.

• Abdominal discomfort.

• Excretion of protein in urine.

• Hypertension.

• Changes in lipid levels in the body.

• Urinary tract infection.

• Difficulty breathing.

• Diarrhea.

• Fever.

• Edema in the peripheries.

• Anemia (A drop in erythrocytes).

• Leukopenia (Reduced leukocytes).

• Blood in urine.

• Cough.

• Increased creatinine levels in the blood.

• Joint pain.

• Back pain.

• Headache.

• Dizziness.

• Tremors.

• Acne.

• Anxiety.

• Hair loss.

• Electrolyte imbalance.

What Are the Precautions to Be Taken Before Taking Belatacept?

• Prior to initiating Belatacept treatment, screening for latent infections, including tuberculosis, hepatitis B virus, and hepatitis C virus, should be done. Treating latent infections before starting Belatacept can help prevent reactivation during immunosuppressive therapy.

• Patients should be up-to-date with all recommended vaccinations before starting Belatacept, as immunosuppression can reduce vaccine efficacy. However, live vaccines should be avoided during Belatacept treatment due to the risk of vaccine-induced infection.

• Belatacept therapy is linked to an elevated risk of EBV-related complications, including post-transplant lymphoproliferative disorder (PTLD). Therefore, patients should be monitored for EBV infection before and during treatment with Belatacept.

• Belatacept is known to cause severe variations in the electrolyte levels in the body. So, serum electrolyte levels should be completely assessed before starting Belatacept to compare and monitor the changes during the treatment.

• Other laboratory hematological tests, such as liver function tests and renal function tests, should be done.

• Belatacept is not advisable to be given to liver transplant individuals.

• The advised regimen should be followed completely, and no dosage should be changed.

For Doctors:

Indications:

• Belatacept is used in individuals who have had a kidney transplant to suppress immune activity.

• Used only in Epstein-Barr virus (EBV) seropositive individuals.

• Belatacept is used along with Basiliximab, Mycophenolate mofetil, and corticosteroids.

• Belatacept may be considered in patients who are at high risk of developing nephrotoxicity from calcineurin inhibitors (such as Cyclosporine or Tacrolimus).

Contraindications:

• Belatacept should not be used for other organ transplants like the liver.

• Individuals who are seronegative to EBV due to the risk of lymphoproliferative disorder development after transplantation.

• Belatacept is contraindicated for use with live vaccines.

• Therapy with Belatacept should not be started if the patient has an active infection.

• Belatacept is not used in people with uncontrolled blood pressure levels.

Drug Ingredients:

Active Ingredient: Belatacept.

Inactive Ingredients: Sucrose, sodium chloride, and monobasic sodium phosphate.

Clinical Pharmacology:

Belatacept, a selective T-cell costimulation blocker, serves as an immunosuppressant utilized in solid organ transplantation, notably kidney transplantation. It binds to CD80 and CD86, inhibiting the interaction with CD28 on T cells, thereby preventing the activation of effector T cells involved in allograft rejection. Unlike traditional immunosuppressive agents such as calcineurin inhibitors, Belatacept does not directly inhibit T-cell function, potentially offering a more targeted approach with less nephrotoxicity.

Half-Life:

The half-life of Belatacept ranges from approximately eight to 12 days.

Pharmacokinetics:

Absorption

As Belatacept is given through intravenous infusion, the drug is absorbed into the bloodstream. The bioavailability of Belatacept is 100 percent.

Distribution

Belatacept's large molecular size limits its distribution to extravascular spaces, where it interacts with its target receptors CD80 and CD86 on antigen-presenting cells, notably dendritic cells, macrophages, and B cells. These interactions prevent the activation of effector T cells involved in allograft rejection. Although Belatacept distributes throughout various tissues, its primary mechanism of action occurs in lymphoid tissues, where it modulates the immune response. Due to its selective targeting of immune cells, belatacept exhibits limited penetration into the central nervous system, reducing the risk of neurological side effects compared to some other immunosuppressive agents.

Metabolism

Belatacept is primarily broken down into smaller peptides and amino acids by proteolytic enzymes present in the body. These enzymes degrade the protein structure of Belatacept into its constituent amino acids.

Elimination

Belatacept is eliminated after filtration through the renal route. The drug and the breakdown products of Belatacept are excreted through urine.

Pharmacodynamics:

Belatacept acts as a selective T-cell costimulation blocker, exerting its pharmacodynamic effects through inhibition of the CD28-mediated co-stimulation pathway, a crucial step in T-cell activation. By binding to CD80 and CD86 on antigen-presenting cells, particularly dendritic cells, macrophages, and B cells, Belatacept prevents the interaction with CD28 on T cells. This interaction blockade interrupts the co-stimulatory signal necessary for T-cell activation, proliferation, and differentiation, thereby dampening the alloimmune response responsible for organ rejection in transplant recipients. Unlike traditional immunosuppressive agents such as calcineurin inhibitors, which globally suppress T-cell function, Belatacept's mechanism of action is more selective, targeting the activation of effector T cells while sparing regulatory T cells. This selective inhibition helps maintain immune surveillance against pathogens while preventing rejection of the transplanted organ.

How Is Belatacept Administered?

• Based on the patient’s body weight, the dosage for Belatacept should be calculated prior to initiation of the therapy, and based on the calculated dose, the number of vials can be used. Each vial contains 250 mg (milligrams) of Belatacept.

• Belatacept should be reconstituted with diluents like sterile water, 0.9 percent sodium chloride, or five percent dextrose.

• The reconstituted formulation of Belatacept should contain 25mg/mL (milligrams per milliliter) and should look colorless to pale yellow.

• This formulation should be infused through an intravenous route. The time taken to complete this administration is around 30 minutes. The drug used infusion must be refrigerated at 35.6 to 46.4 degrees Fahrenheit (two to eight degrees Celsius).

Clinical Toxicity:

• The probability of acquiring infections, including bacterial, viral, and fungal agents, is very high due to marked immunosuppression after administration of Belatacept.

• Post-transplant lymphoproliferative disorder and lymphoma are common after taking Belatacept. This is specifically common in people with Epstein-Barr virus seronegativity.

• Other viral infections can attack any vital organs in the body, along with the transplanted kidney. This can lead to dysfunction of organs and organ systems.

• When a viral agent like the JC virus affects the brain structure, there can be inflammation in the white matter and myelin-forming cells. This leads to proliferative multifocal leukoencephalopathy.

• Blood pressure levels can become uncontrolled.

• Belatacept use may lead to hematologic abnormalities, such as anemia or thrombocytopenia, requiring monitoring of blood counts.

Drug Interactions:

• Belatacept should not be given with other immunosuppressants as it can cause severe suppression of immune activity in the body, leading to pancytopenia and lymphoproliferative disorders.

• Nephrotoxic drugs like non-steroidal anti-inflammatory agents or antibiotics should not be given with Belatacept as it can lead to Belatacept-induced nephropathy and result in dysfunctional kidneys.

Use in Specific Populations:

Pregnancy and Lactation

Belatacept is a category C drug, and it is not indicated for use in pregnant women as there is evidence regarding the harmfulness of Belatacept on the fetus. Similarly, there is limited information on the excretion of belatacept into breast milk, and its effects on nursing infants are unknown. Therefore, breastfeeding is not recommended while receiving belatacept treatment.

Geriatric Individuals

Geriatric people with hypertension or other comorbidities are not advised for Belatacept use.

Pediatric Population

Belatacept can cause autoimmunity in people under 18 years of age as there is development of T cells till that age.

Precautions:

• Individuals who are given Belatacept should have undergone a complete hematological examination and should have been checked for infectious state.

• After administering Belatacept, if there are changes in the walking pattern, cognition, or sleeping cycles, progressive multifocal leukoencephalopathy should be suspected, and immediate examination of cerebrospinal fluid and brain biopsy should be done.

• Any infections post-transplantation should be treated immediately.