A pharmacokinetic and clinical assessment of tofacitinib for the treatment of rheumatoid arthritis

Abstract

Tofacitinib is an oral synthetic DMARD displaying linear pharmacokinetics. Metabolism, primarily mediated by CYP3A4, accounts for 70% of the total clearance of the drug; the remaining 30% are renally excreted. Tofacitinib monotherapy, or in combination with traditional DMARDs, has demonstrated its efficacy while having an acceptable safety profile in RA patients who have responded inadequately to current DMARDs, including TNF antagonists. In view of its undetermined benefit to risk ratio, in the real-world population, tofacitinib should, for now, only be prescribed to selected patients.

Analysis of patents on anti-rheumatoid arthritis therapies issued in China

“…The JAK/STAT pathways have been implicated in the pathogenesis of inflammatory diseases, such as RA [53]. Tofacitinib, a JAK inhibitor, is the first oral non-biologic DMARD approved by the US FDA [54] in 2012.…”

A novel approach in treatment of rheumatoid arthritis: Janus kinase inhibitors

“…Most of the drug is metabolized by cytochrome P3A4 enzyme and rest is excreted renally. 12 It has been shown to be superior than placebo when given as an add-on therapy to methotrexate receiving patients with RA. 13 In an ORAL SOLO trial, the effect of tofacitinib was seen in the patients with RA, but the effect was not signifi cant, indicating that though it might be effective as a monotherapy, but for remission, additional DMARD therapy is required.…”

Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis

“…Cytokine signaling, pro-inflammatory cytokine production and immune cell activation are key functions of activated JAK in the perpetuation of autoimmune inflammatory disease [3] . The JAK family, JAK1, JAK 2, JAK 3 and Tyk2, are nonreceptor tyrosine kinases with a variety of intercellular domains, a pseudokinase domain, and SH2-and FERM domains [4] .…”

“…This leads to increased JAK activity, further recruitment of cytokines, and changes in gene expression through JAK-STAT pathway. The synovium of RA patients has increased expression of the JAK-STAT pathway [3] . JAK1 and JAK2 play a role in growth, neurodevelopment, hematopoiesis, and host defense while JAK3 and Tyk2 are engaged in immune responses.…”

“…Inhibition of JAKs is responsible for decreased pro-inflammatory cytokines signaling via IL-2 and IL-4 inhibition, decreased IL-6 production by synovial fibroblasts, decreased receptor activator of nuclear factor-κB ligand production, decreased IL-8 production by CD14 + monocytes, and decreased production of TNF-stimulated fibroblast-like synoviocytes. The net effect of tofacitinib is decreased synovial inflammation and structural joint damage in RA patients by limiting T cell and other leukocyte recruitment [3] . Other immune cells involved in RA pathogenesis express JAKs and may also be affected by tofacitinib inhibition.…”