Belatacept

A Novel Biologic for Maintenance Immunosuppression After Renal Transplantation

Spencer T. Martin, Pharm.D.; Eric M. Tichy, Pharm.D.; Steven Gabardi, Pharm.D.

Disclosures

Pharmacotherapy. 2011;31(4):394-407. 

In This Article

Chemistry

Pharmacology

Belatacept is a more potent, second-generation molecule of its parent compound, abatacept. Abatacept is a biologic that also has antagonistic effects on CD80 and CD86 and has been approved by the FDA for the treatment of autoimmune disease, specifically rheumatoid arthritis.[35–40] It was determined that abatacept binds to CD80 with a 2500-fold higher affinity and to CD86 with a 500-fold higher affinity compared with the CD28 cell surface marker of naive T cells. The theory that abatacept would have a role in renal transplantation was tested in mice and showed relative promise; however, subsequent analyses resulted in poor outcomes in nonhuman primate renal transplant models.[41–43] With a seemingly impressive affinity to the B-7 ligands, the difference in antagonistic effect to CD80 compared with CD86 results in a 100-fold decrease in affinity to the CD86. Therefore, a complete and equal block of the costimulation pathway is not achieved.[44,45]

The consensus that abatacept was not appropriate for solid organ transplantation because of its relatively weak affinity led to the development of a more effective agent. Belatacept was produced by altering two amino acids in the B-7 ligand–binding portion of the abatacept molecule, which resulted in a 4-fold increase in binding affinity to CD86 and a 2-fold increase in CD80 binding affinity in comparison to abatacept. This increase in binding affinity to the B-7 ligand family resulted in a 10-fold increase in inhibiting T-cell activation when compared with abatacept in vitro.[43] The dramatic increase seen in vitro directly correlated with improved renal allograft outcomes in a nonhuman primate renal transplant model.[43]

During belatacept's phases II and III studies, a separate analysis was performed to assess the level of saturation obtained at the CD80 and CD86 receptors when administering varying doses of belatacept.[46] Both free and total CD86 were measured before and after belatacept infusions in participating renal transplant recipients. It was determined that CD80 and CD86 receptors become saturated through a concentration-dependent pathway. The CD80 saturation occurs at a much lower level, 0.1 μg/ml, whereas complete CD86 saturation requires a 10-fold increase in concentration to occur (1.0 μg/ml). The authors suggested that alloresponse would be appropriately inhibited only at the concentrations required to saturate CD86, rather than the lower concentrations needed to inhibit CD80. These results suggest that measurements of CD86 occupancy by the belatacept molecule may be an appropriate measurement of immune inhibition and the pharmacodynamic effect of the drug on a patient-by-patient basis in the future.

The route of administration for belatacept is distinctive in that it is the first long-term intravenous maintenance therapy for solid organ transplantation. Typically, maintenance drugs such as cyclosporine, tacrolimus, mycophenolate mofetil, mycophenolic acid, sirolimus, azathioprine, and corticosteroids are administered orally. Belatacept requires that a patient receive intermittent infusions to maintain adequate immunosuppression. Infusions of belatacept are required relatively frequently during the period immediately after transplantation, but eventually taper to once/month by the end of the first or third month, depending on the dosage regimen chosen. The two most commonly studied dosing schemes for belatacept are described more completely in Table 1.[47–49] Although the intravenous route of administration might be distinctive for transplantation maintenance therapy, other intravenous biologic drugs are routinely used to manage chronic disease states, for example, rheumatoid arthritis. One benefit described as a result of mandatory infusions is assured adherence to the belatacept component of immunosuppressive therapy because a missed appointment for an infusion is recognized immediately by clinicians.[50]

Pharmacokinetics

Because of an increased time to clearance and volume of central compartment as patient weight increases, belatacept is dosed based on total body weight.[51] Pharmacokinetic parameters were not found to be influenced by sex, age, race-ethnicity, or comorbid conditions. Belatacept's pharmacokinetics were determined to be linear, with zero-order intravenous infusion and first-order elimination with the standard dose range of 5–10 mg/kg. The pharmacokinetics of belatacept are not influenced by hemodialysis, renal insufficiency, or hepatic dysfunction, indicating no need for dosage adjustments. The expected half-life of belatacept is about 11 days.

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