Chemical formula: C₃₄₉₈H₅₄₅₈N₉₂₂O₁₀₉₀S₃₂ Molecular mass: 92,300 g/mol
Abatacept selectively modulates a key costimulatory signal required for full activation of T lymphocytes expressing CD28. Full activation of T lymphocytes requires two signals provided by antigen presenting cells: recognition of a specific antigen by a T cell receptor (signal 1) and a second, costimulatory signal. A major costimulatory pathway involves the binding of CD80 and CD86 molecules on the surface of antigen presenting cells to the CD28 receptor on T lymphocytes (signal 2). Abatacept selectively inhibits this costimulatory pathway by specifically binding to CD80 and CD86. Studies indicate that naive T lymphocyte responses are more affected by abatacept than memory T lymphocyte responses.
Studies in vitro and in animal models demonstrate that abatacept modulates T lymphocyte-dependent antibody responses and inflammation. In vitro, abatacept attenuates human T lymphocyte activation as measured by decreased proliferation and cytokine production. Abatacept decreases antigen specific TNFα, interferon-γ, and interleukin-2 production by T lymphocytes.
Abatacept is a fusion protein that 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). Abatacept is produced by recombinant DNA technology in Chinese hamster ovary cells.
Dose-dependent reductions were observed with abatacept in serum levels of soluble interleukin-2 receptor, a marker of T lymphocyte activation; serum interleukin-6, a product of activated synovial macrophages and fibroblast-like synoviocytes in rheumatoid arthritis; rheumatoid factor, an autoantibody produced by plasma cells; and C-reactive protein, an acute phase reactant of inflammation. In addition, serum levels of matrix metalloproteinase-3, which produces cartilage destruction and tissue remodelling, were decreased. Reductions in serum TNFα were also observed.
The geometric mean estimate (90% confidence interval) for the bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6% (64.7%, 95.6%). The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration.
A single study was conducted to determine the effect of monotherapy use of abatacept on immunogenicity following subcutaneous administration without an intravenous load. When the intravenous loading dose was not administered, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing. The efficacy response over time in this study appeared consistent with studies that included an intravenous loading dose, however, the effect of no intravenous load on the onset of efficacy has not been formally studied.
Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant MTX, NSAIDs, corticosteroids, and TNF-inhibitors did not influence abatacept apparent clearance.
In PsA-I, patients were randomized to receive IV placebo or abatacept 3 mg/kg (3/3 mg/kg), 10 mg/kg (10/10 mg/kg), or two doses of 30 mg/kg followed by 10 mg/kg (30/10 mg/kg), on Day 1, 15, 29, and then every 28 days thereafter. In this study, the steady-state concentrations of abatacept were doserelated. The geometric mean (CV%) Cmin at Day 169 were 7.8 mcg/mL (56.3%) for the 3/3 mg/kg, 24.3 mcg/mL (40.8%) for 10/10 mg/kg, and 26.6 mcg/mL (39.0%) for the 30/10 mg/kg regimens. In study PsA-II following weekly SC administration of abatacept at 125 mg, steady-state of abatacept was reached at Day 57 with the geometric mean (CV%) Cmin ranging from 22.3 (54.2%) to 25.6 (47.7%) mcg/mL on Days 57 to 169, respectively.
Consistent with the results observed earlier in RA patients, population pharmacokinetic analyses for abatacept in PsA patients revealed that there was a trend toward higher clearance (L/h) of abatacept with increasing body weight.
No mutagenicity or clastogenicity was observed with abatacept in a battery of in vitro studies. In a mouse carcinogenicity study, increases in the incidence of malignant lymphomas and mammary gland tumours (in females) occurred. The increased incidence of lymphomas and mammary tumours observed in mice treated with abatacept may have been associated with decreased control of murine leukaemia virus and mouse mammary tumour virus, respectively, in the presence of long-term immunomodulation. In a one-year toxicity study in cynomolgus monkeys, abatacept was not associated with any significant toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centres in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphological changes was observed, despite the presence of a virus, lymphocryptovirus, which is known to cause such lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of abatacept is unknown.
In rats, abatacept had no undesirable effects on male or female fertility. Embryo-foetal development studies were conducted with abatacept in mice, rats, and rabbits at doses up to 20 to 30 times a human 10 mg/kg dose and no undesirable effects were observed in the offspring. In rats and rabbits, abatacept exposure was up to 29-fold a human 10 mg/kg exposure based on AUC. Abatacept was shown to cross the placenta in rats and rabbits. In a pre- and postnatal development study with abatacept in rats, no undesirable effects were observed in pups of dams given abatacept at doses up to 45 mg/kg, representing 3-fold a human 10 mg/kg exposure based on AUC. At a dose of 200 mg/kg, representing 11-fold a human exposure at 10 mg/kg based on AUC, limited changes in immune function (a 9-fold increase in the mean T-cell-dependent antibody response in female pups and inflammation of the thyroid of 1 female pup out of 10 male and 10 female pups evaluated at this dose) were observed.
Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (juvenile rats). In addition, inflammation of the thyroid and pancreas was frequently seen in both juvenile and adult rats exposed to abatacept. Juvenile rats seemed to be more sensitive to lymphocytic inflammation of thyroid. Studies in adult mice and monkeys have not demonstrated similar findings. It is likely that the increased susceptibility to opportunistic infections observed in juvenile rats is associated with the exposure to abatacept before development of memory responses. The relevance of these results to humans greater than 6 years of age is unknown.
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