| Primary information |
|---|
| ThPP ID | Th1102 |
| Therapeutic Peptide/Protein Name | Abatacept |
| Sequence | MHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAA view full sequnce in fasta |
| Functional Classification | IIa |
| Molecular Weight | 92300 |
| Chemical Formula | C3498H5458N922O1090S32 |
| Isoelectric Point | N.A. |
| Hydrophobicity | N.A. |
| Melting Point (℃) | N.A. |
| Half Life | 16.7 (12-23) days in healthy subjects |
| Description | Recombinant (CHO cell derived), soluble fusion protein that links the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), to the modified Fc (hinge, CH2, and CH3 domains) portion of human IgG1. Abatacept is a glycosylated fusion protein with molecular weight of 92,300 Da and it is a homodimer of two polypeptide chains of 357 amino acids. The drug has activity as a selective co-stimulation modulator with inhibitory activity on T lymphocytes. |
| Indication/Disease | For the management of the signs and symptoms of moderate-to-severe active rheumatoid arthritis, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adult patients. It is indicated both as a monotherapy and for use in combination with a continued regimen of DMARDs (not including TNF antagonists). Also used for the management of the signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in children. |
| Pharmacodynamics | Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G1 (IgG1. The Fc portion of the drug consists of the hinge region, the CH2 domain, and the CH3 domain of IgG1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. |
| Mechanism of Action | Abatacept is a selective costimulation modulator, like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. |
| Toxicity | Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. |
| Metabolism | N.A. |
| Absorption | When a single 10 mg/kg Intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. |
| Volume of Distribution | 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] |
| Clearance | 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous infusion 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients].The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients.The clearance of abatacept increases with increasing body weight. |
| Categories | Antirheumatic Agents and Immunosuppressive Agents |
| Patents Number | CA2110518 |
| Date of Issue | 23/05/11 |
| Date of Expiry | 17/06/16 |
| Drug Interaction | N.A. |
| Target | T-lymphocyte activation antigen CD80,T-lymphocyte activation antigen CD86 |
| Information of corresponding available drug in the market |
|---|
| Brand Name | ORENCIA |
| Company | Bristol-Myers Squibb |
| Brand Discription | ORENCIA (abatacept) 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). Abatacept is produced by recombinant DNA technology in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons. |
| Prescribed for | Adult Rheumatoid Arthritis (RA): ORENCIA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. ORENCIA may be used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists.; Juvenile Idiopathic Arthritis: ORENCIA is indicated for reducing signs and symptoms in pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis. ORENCIA may be used as monotherapy or concomitantly with methotrexate |
| Chemical Name | N.A. |
| Formulation | Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for Injection, USP, the solution of ORENCIA is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of ORENCIA provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration. |
| Physcial Appearnce | Lyophilized powder for Intravenous infusion is supplied as a Sterile, white, preservative-free, lyophilized powder for intravenous administration |
| Route of Administration | Intravenous infusion, Subcutaneous Injection |
| Recommended Dosage | Adult Rheumatoid Arthritis, For adult patients with RA, ORENCIA may be administered as an Intravenous infusion or a subcutaneous injection. ORENCIA may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists. For pediatric juvenile idiopathic arthritis, a dose calculated based on each patient's body weight is used. Intravenous Dosing Regimen; ORENCIA intravenous should be administered as a 30-minute Intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, an Intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. |
| Contraindication | N.A. |
| Side Effects | The most serious adverse reactions were serious infections and malignancies. The most commonly reported adverse events (occurring in ≥ 10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea. |
| Useful Link | http://www.rxlist.com/orencia-drug.htm http://www.drugs.com/pro/orencia.html http://www.webmd.com/drugs/2/drug-94819/orencia-iv/details |
| PubMed ID | 20080922, 19821401, 18041889, 17212998, 17014006, 16971318, 16932686, 16573350, 16557658 |
| 3-D Structure | N.A. |