Although other doses have been studied, the recommended dose of tofacitinib is 5 mg twice daily. Total serum immunoglobulins were not assessed in patients with active psoriatic arthritis.Ĭlinical Studies: The tofacitinib clinical development program included two dose-ranging trials and five confirmatory trials. Similar changes in T cells, B cells, and serum CRP have been observed in patients with active psoriatic arthritis although reversibility was not assessed. Changes in CRP observed with tofacitinib treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life. Total serum IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis were lower than placebo however, changes were small and not dose-dependent.Īfter treatment with tofacitinib in patients with rheumatoid arthritis, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. The clinical significance of these changes is unknown. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. Treatment with tofacitinib was associated with dose-dependent increases in B cell counts. These changes generally resolved within 2-6 weeks after discontinuation of treatment. Pharmacodynamics: Treatment with tofacitinib was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8-10 weeks after initiation of therapy. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known. Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC 50 of 406, 56, and 1377 nM, respectively. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Pharmacology: Mechanism of Action: Tofacitinib is a Janus kinase (JAK) inhibitor.
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