Belatacept (Belataceptum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Immunosuppressive drugs

Included in the formulation
АТХ:

L.04.A   Immunosuppressive drugs

Pharmacodynamics:

Belotacept is a selective blocker of co-stimulation of T-lymphocytes.

Belatacept is a soluble protein consisting of a modified extracellular domain of antigen-4 cytotoxic T-lymphocytes (CTLA-4), in which two amino acids (leucine in 104 positions for glutamic acid, alanine in 29 positions for tyrosine) with part of the Fc fragment of human immunoglobulin Gl (IgGl). Belatacept is a recombinant protein obtained using genetic engineering techniques on the isolated culture of mammalian cells. Belatacept selectively modulates the key co-stimulatory signal necessary for the complete activation of T lymphocytes. Activated T-lymphocytes are the main mediators of the immunological response to the rejection of the transplanted organ. To fully activate T-lymphocytes, 2 signals from antigen-presenting cells are required: the first - through the recognition of a specific antigen by T-cell receptors (signal 1); a second (nonspecific) co-stimulating signal by binding CD80 and CD86 molecules expressed on the surface membrane to CD28 receptors expressed on the T lymphocyte membrane. Belatacept specifically blocks the interaction of CD28 with CD80 and CD86, selectively inhibiting the key co-stimulatory signal necessary for the activation of T lymphocytes. As a result of modification of the fragment CTLA-4 belatacept more actively binds to CD80 and CD86 molecules than the original form of CTLA4-IgG1. This allows to achieve the level of immunosuppression necessary to suppress the rejection of the transplant and prevent its dysfunction.

In vitro studies belatacept inhibited the proliferation of T-lymphocytes and reduced the production of cytokines (interleukin-2, interferon-γ, interleukin-4 and TNF-alpha). Inhibition of the response of T-lymphocytes to the allogeneic antigen is the most important factor in preventing graft rejection. In pre-clinical studies on kidney transplants in primates belatacept in the form of monotherapy or in combination with standard therapy significantly increased the graft lifetime in comparison with placebo, reducing the production of antibodies against the antigens of the donor organ.

Pharmacokinetics:

The pharmacokinetics of belatacept in healthy volunteers and in patients with a transplanted kidney is comparable.

With a single intravenous infusion of healthy volunteers, a proportional increase in Cmax and AUC (area under the concentration-time curve) was observed in the dose range from 1 mg / kg to 20 mg / kg. Concentration in the serum achieves an equilibrium state at week 8 when assigned in the early posttransplant period and remains stable with constant therapy for 6 months. In determining 1, 4 and 6 months after transplantation, the mean values ​​of the minimum concentration were 22.7 (11.1 - 45.2) μg / ml, 7.6 (2.1-18.0) μg / ml and 4.0 (1.5-6.6 μg / ml, respectively).

The pharmacokinetics of belatacept did not change with its use for 1 year after kidney transplantation. The minimum concentrations of belatacept were maintained for 5 years after transplantation against the background of the recommended regimen of therapy with belatacept.

Systemic cumulation of belatacept in the body was minimal with prolonged repeated administration of the drug in a dose of 5-10 mg / kg at intervals of 1 month.

Pharmacokinetics in specific categories of patients.

It was found that higher clearance of belatacept is observed in patients with increased body weight.

Age, sex, race, kidney function (assessment of the value of glomerular filtration), liver function (evaluation of albumin concentration), diabetes mellitus, and dialysis sessions do not affect the clearance of belatacept.

Indications:

Prevention of graft rejection after kidney transplantation (in combination with induction with basiliximab, and also in combination with mycophenolate mofetil and corticosteroids).

ICD-10

XXI.Z80-Z99.Z94   Presence of transplanted organs and tissues

Contraindications:

Patients with seronegative status or unknown status in relation to the Epstein-Barr virus, hypersensitivity to belatacept.

Carefully:

No data.

Pregnancy and lactation:

It should not be used during pregnancy, except when the expected benefit of therapy for the mother exceeds the potential risk to the fetus.

Clinical studies of use in pregnancy have not been conducted.

It is not known whether belatacept with human breast milk in humans and absorbed in the body of a child with breast milk. If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

It is used only in patients with seropositive reaction to the Epstein-Barr virus.

Enter intravenously in the form of infusion.

The dose is set individually according to the patient's true body weight during transplantation and can not be modified during the course of treatment, except when the body weight changes by more than 10%.

In the initial phase of treatment, the dose is 10 mg / kg, in the maintenance phase - 5 mg / kg.

The dose is calculated individually according to a special scheme.

Duration of treatment is set individually.

Side effects:

On the part of the digestive system: ≥ 20% - diarrhea, constipation, nausea, vomiting; ≥ 10% - abdominal pain; <10% - stomatitis (including aphthous).

On the part of the hematopoiesis system: ≥ 20% - anemia, leukopenia; <10% - neutropenia.

From the urinary system: ≥ 20% - urinary tract infections; ≥ 10% - hematuria, proteinuria, dysuria, renal tubular necrosis, increased serum creatinine content; <10% - renal disorders, including renal artery stenosis, urinary incontinence, hydronephrosis.

From the cardiovascular system: ≥ 20% - hypertension; ≥ 10% - arterial hypotension; <10% - hematoma, lymphocele, atrial fibrillation.

From the respiratory system: ≥ 20% - cough; ≥ 10% - infections of the upper respiratory tract, nasopharyngitis, bronchitis, dyspnea.

From the central nervous system: ≥ 20% - headache; ≥ 10% - dizziness, tremor, anxiety, insomnia.

From the side of metabolism: hypokalemia, hyperkalemia, diabetes mellitus; ≥ 10% - hypophosphatemia, dyslipidemia, hyperglycemia, hypocalcemia, hypercholesterolemia, hypomagnesemia, hyperuricemia.

From the musculoskeletal system: ≥ 10% - arthralgia, back pain; <10% - musculoskeletal pain

From the skin: ≥ 10% - acne; <10% - alopecia, hyperhidrosis.

Tumor diseases: a post-transplant lymphoproliferative disease that primarily affects the central nervous system, non-melanoma skin cancer, and other malignant diseases.

Infections: progressive multifocal leukoencephalopathy associated with JC virus, nephropathy due to polyomavirus, fungal infection, infections caused by the herpes virus, tuberculosis, infectious diseases of the central nervous system, cytomegalovirus infection.

Immunological reactions: it is possible the formation of antibodies to belatacept, incl.neutralizing (clinical value not determined); <10% - Guillain-Barre syndrome.

From the side of the transplant: ≥ 20% - a violation of the function; <10% - chronic nephropathy associated with allograft, complications from the transplanted kidney, including the divergence of the edges of the wound, thrombosis of arteriovenous fistula.

Common reactions: ≥ 20% - peripheral edema; infusion reactions.

Reasons for drug cancellation: 1,5% - cytomegalovirus infection, complications after kidney transplantation.

Overdose:

No data.

Interaction:

In patients with a kidney transplant receiving belatacept, symptoms of impaired efficacy or side effects were observed with simultaneous administration of drugs metabolized with the participation of CYP450 isoenzymes. Such combinations should be used with caution.

In pharmacokinetic studies in patients receiving mycophenolate mofetil 500-1500 mg twice daily with belatacept at a dose of 5 mg / kg or with cyclosporine, it was found that the mean maximum the concentration of a substance in blood plasma and Area under the curve of the curve (area under curve) "concentration - time" (AUC0-12) Mycophenolic acid was 20% and 40%, respectively, more when combined with belatacept than with cyclosporine. It should be borne in mind a possible change in the bioavailability of mycophenolic acid after the transition from belatacept to ciclosporin or vice versa in patients receiving mycophenolate mofetil.

Special instructions:

Contraindicated use belatatsepta in patients with seronegative or unknown status, t. risk of development Post-transplant lymphoproliferative disease, mainly affecting the central nervous system, is higher in patients with a seronegative response to the Epstein-Barr virus, compared to patients with a seropositive response to the Epstein-Barr virus.

Prior to the use of belatacept, the serological status of the patient with respect to the Epstein-Barr virus should be determined. Belatacept It can be used only in patients with a seropositive response to the Epstein-Barr virus.

Before starting the use of belatacept, samples for tuberculosis status should be performed.

Because immunosuppression is a risk factor for development Post-transplant lymphoproliferative disease, progressive multifocal leukoencephalopathy, as well as serious infections, belatacept Do not use in doses exceeding recommended and more often than recommended.

Other risk factors for development Post-transplant lymphoproliferative disease is a cytomegalovirus infection and therapy with drugs that depress T cell activity.

In patients receiving belatacept, increased risk of developing post-transplant lymphoproliferative disease, mainly involving the central nervous system, compared with patients receiving ciclosporin.

The doctor should presume development Post-transplant lymphoproliferative disease, progressive multifocal leukoencephalopathy when there are or worsen neurological, cognitive symptoms, behavioral disorders.

In the treatment of immunosuppressants, including belatacept, increased risk of malignant neoplasms, including skin. Therefore, during treatment, patients should avoid exposure to sunlight and ultraviolet radiation.

Within 3 months after transplantation, the prevention of cytomegalovirus infection is recommended.

After transplantation, prevention of infection caused by Pneumocystis jiroveci.

Patients should be monitored for the detection of symptoms of poliomyoviral nephropathy, which can lead to serious consequences - impaired renal function and loss of kidney graft.

When using belatacept, immunization with live vaccines should be avoided.

Instructions
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