DESCRIPTION
Abatacept (trade name Orencia®) is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) linked to the modified Fc (hinge, CH2 and CH3 domains) portion of human immunoglobulin G1 (IgG1).
CLASSIFICATION
Abatacept is the first in a new class of agents known as selective costimulation modulators (Abatacept: A Novel Treatment for Moderate-to-Severe Rheumatoid Arthritis, 2007).
INDICATIONS
The U.S. Food and Drug Administration approved abatacept for reducing signs and symptoms, inducing major clinical response, slowing the progression of structural damage and improving physical function in adults with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to at least one other DMARD, such as methotrexate or a TNF-a inhibitor. It is also being used off-label to treat patients with an overlap of both systemic lupus erythematosus and rheumatoid arthritis. Abatacept may be used in combination with methotrexate or other traditional DMARD therapy, but concurrent therapy with other biologic DMARDs is not recommended (Abatacept: A Novel Treatment for Moderate-to-Severe Rheumatoid Arthritis, 2007).
In the USA and Europe, abatacept is also recommended for treatment of active polyarticular juvenile idiopathic arthritis in patients aged ≥6 years as monotherapy or with MTX. In Europe, abatacept is also approved in patients who have insufficient response to other DMARDs, including at least one TNFi (Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012, 2013).
PHARMACOKINETICS
The pharmacokinetics of abatacept have been demonstrated to be dose-proportional and linear.
The clearance of abatacept is unaffected by sex (when corrected for body weight) and age (Abatacept: A Novel Treatment for Moderate-to-Severe Rheumatoid Arthritis, 2007).
Concomitant methotrexate, NSAIDs, corticosteroids and TNF blocking agents did not influence abatacept clearance (Orencia).
PHARMACODYNAMICS
In clinical trials with abatacept at doses approximating 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3) and TNFα. The relationship of these biological response markers to the mechanisms by which abatacept exerts its effects in RA is unknown (Orencia).
MOLECULAR MECHANISM
Abatacept selectively modulates T-cell activation.
Normal T-cell activation requires two signals.
The first signal occurs when an antigen within the major histocompatibility complex class II molecule on an antigen-presenting cell binds to a specific T-cell receptor on the T cell.
A second signal or costimulatory signal occurs when CD28 on the T cells binds to CD80 or CD86 on the antigen-presenting cell. The cytotoxic T-lymphocyte–associated antigen-4 is a naturally occurring inhibitor of this interaction expressed on the surface of T cells after activation. It binds to CD80 and CD86 much more avidly than does CD28. Binding of abatacept to CD80 and CD86 effectively prevents the second CD28-CD80/86 costimulatory signal from optimally activating T cells (Abatacept: A Novel Treatment for Moderate-to-Severe Rheumatoid Arthritis, 2007).
In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF-alpha (TNFα), interferon-γ (INF-y) and interleukin-2 (IL-2).
In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production and reduces antigen specific production of INF-γ. The relationship of these biological response markers to the mechanisms by which abatacept exerts its effects in RA is unknown (Orencia).
DOSING AND ADMINISTRATION
Abatacept is provided as 250 mg of lyophilized powder in a preservative-free, single-use 15-ml vial that must be reconstituted before administration with 10 ml of sterile water for injection. Abatacept should be administered as a 30-minute intravenous infusion according to body weight range.
Abatacept should not be infused concomitantly in the same intravenous line with other agents. In clinical trials, doses up to 50 mg/kg have been administered without apparent toxic effects (Abatacept: A Novel Treatment for Moderate-to-Severe Rheumatoid Arthritis, 2007).
SIDE EFFECTS AND TOXICITY
Possible serious side effects of abatacept are:
- Serious infections: abatacept can make the patient more likely to get infections and some of them have died from these infections.
- Allergic reactions: they can happen on the day of treatment or the day after receiving abatacept: hives, swollen face, eyelids, lips, tongue or trouble breathing.
- Vaccinations: abatacept may cause some vaccinations to be less effective because of its mechanism of action.
- Respiratory problems in patients with COPD: certain respiratory problems become more recurring if patients receive abatacept and have COPD, including: worsened COPD, pneumonia, cough or trouble breathing.
- Cancer (malignancies): certain kinds of cancer have been reported in patients receiving abatacept, but it’s not known if this treatment increases the chance of getting this malignancies.
Common side effects with abatacept are:
- Upper respiratory tract (URT) infection
(Orencia)
DRUG-DRUG INTERATIONS
Glycoproteins, such as abatacept, do not have specific interactions with molecules that are metabolized by the liver and pharmacokinetic analyses revealed that nonsteroidal antiinflammatory drugs (NSAIDs), methotrexate, corticosteroids and TNF-a inhibitors do not influence abatacept clearance. Methotrexate and other nonbiologic DMARDs, corticosteroids, salicylates, NSAIDs or analgesics may be used during treatment with abatacept.
In controlled clinical trials, patients receiving therapy experienced more infections and serious infections compared with patients treated with only TNF-a inhibitors. As such, concurrent therapy with abatacept and a TNF-a inhibitor is not recommended, and there is insufficient experience to assess the safety and efficacy of abatacept in combination with anakinra (Abatacept: A Novel Treatment for Moderate-to-Severe Rheumatoid Arthritis, 2007).
Parenteral drug products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in abatacept formulation for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving abatacept through intravenous administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods (Orencia).
DEPENDENCE AND WITHDRAW
There isn’t any important evidence about dependence and withdraw.
Author:
Francesca Martinetto
