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Tofacitinib.

ABSTRACT: Tofacitinib (CP-690,550; CP-690550; CP690550), an orally active immunosuppressant, is being developed by Pfizer for the treatment of rheumatoid arthritis, inflammatory bowel disease, dry eyes, ankylosing spondylitis, psoriasis, psoriatic arthritis, and for the prevention of transplant rejection. Tofacitinib specifically inhibits Janus activated kinase 3 (JAK3), which has a pivotal role in cytokine signal transduction that governs lymphocyte survival, proliferation, differentiation, and apoptosis. This review discusses the key development milestones and therapeutic trials of this drug.

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PROVIDER: S-EPMC3585773 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Tofacitinib.

Drugs in R&D 20100101 4

Tofacitinib (CP-690,550; CP-690550; CP690550), an orally active immunosuppressant, is being developed by Pfizer for the treatment of rheumatoid arthritis, inflammatory bowel disease, dry eyes, ankylosing spondylitis, psoriasis, psoriatic arthritis, and for the prevention of transplant rejection. Tofacitinib specifically inhibits Janus activated kinase 3 (JAK3), which has a pivotal role in cytokine signal transduction that governs lymphocyte survival, proliferation, differentiation, and apoptosis ...[more]

PMID: 21171673

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Tofacitinib reduces mortality in coronavirus disease 2019 Tofacitinib in COVID-19.

Project description:Background and aimCytokine release syndrome is a dangerous complication of the coronavirus disease 2019 (COVID-19). This study aimed to evaluate the efficacy and safety of tofacitinib in the management of this complication.MethodsThe retrospective study included COVID-19 patients with C-reactive protein (CRP) levels of 60-150 mg/L.ResultsThirty-two patients who received tofacitinib (TOF group) and 30 patients who did not receive any anti-cytokine drugs (control [CON] group) were enrolled. Mortality and the incidence of admission to the intensive care unit were lower in the TOF group than in the CON group (16.6% vs. 40.0%, p = 0.009; and 15.6% vs. 50.0%, p = 0.004). There was a significant decrease in the volume of the affected part of the lungs (p = 0.022) and a significant increase in oxygen saturation (p = 0.012) in the TOF group than in the CON group 7-10 days after the beginning tofacitinib administration. CRP level was lower in the TOF group than in the CON group (7 [3-22] vs. 20 [5-52] mg/L; p = 0.048) 7-10 days after the start of the administration of tofacitinib. During this period, the number of patients requiring mechanical ventilation or those in the prone position increased in the CON group compared to those in the TOF group (26.7% vs. 0.0%, p = 0.002; 33.3% vs. 6.7%, p = 0.020). There was no significant difference in the development of secondary infections, liver or kidney injury, and cytopenia between the two groups.ConclusionTofacitinib was effective and safe for managing the cytokine release syndrome in COVID-19. Randomized controlled double-blind trials with tofacitinib with and without the simultaneous use of glucocorticoids are required to confirm our findings.

| S-EPMC8137353 | biostudies-literature

Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects.

Project description:Tofacitinib is an oral disease-modifying anti-rheumatic drug to selectively inhibit Janus kinases. Tofacitinib is a representative small molecule inhibitor that is used to treat many diseases including rheumatoid arthritis and various autoimmune conditions. Unlike biological agents, tofacitinib has several advantages, including the ability to be administered orally and a short half-life. This study aimed to evaluate the bioequivalence of the pharmacokinetics (PK) between tofacitinib aspartate 7.13 mg (test formulation) and tofacitinib citrate 8.08 mg (reference formulation; Xeljanz®) in healthy subjects. A randomized, open-label, single-dose, 2-sequence, 2-period, 2-treatment crossover trial was conducted in 41 healthy volunteers. A total of 5 mg of tofacitinib as the test or the reference formulation was administered, and serial blood samples were collected up to 14 hours after dosing for PK analyses. The plasma concentration of tofacitinib was determined by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental analysis was used to estimate the PK parameters. A total of 35 subjects completed the study and the study drug was well-tolerated. The mean maximum concentration (Cmax) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) for the test formulation were 52.67 ng/mL and 133.86 ng?h/mL, respectively, and 50.61 ng/mL and 133.49 h?ng/mL for the reference formulation, respectively. The geometric mean ratios (90% confidence intervals) of the Cmax and AUClast between the 2 formulations were 1.041 (0.944-1.148) and 1.003 (0.968-1.039), respectively. Tofacitinib aspartate exhibited bioequivalent PK profiles to those of the reference formulation. Trial Registration:ClinicalTrials.gov Identifier: NCT04278391.

| S-EPMC7533161 | biostudies-literature

Treatment of Multiorgan Sarcoidosis With Tofacitinib.

Project description:OBJECTIVE:Sarcoidosis is an idiopathic inflammatory disorder that is difficult to treat. There is accumulating evidence that constitutive activation of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling occurs in sarcoidosis and represents a target for treatment. Here we report the efficacy of tofacitinib, a Janus kinase (JAK) inhibitor, in a single patient with multiorgan sarcoidosis. METHODS:A patient with long-standing multiorgan sarcoidosis who was unresponsive to other commonly used therapies, including methotrexate, prednisone, and tumor necrosis factor α blockade, was treated with tofacitinib. RESULTS:Tofacitinib treatment resulted in clinical remission of cutaneous sarcoidosis lesions and resolution of positron emission tomography avid lesions in internal organs after 6 months. An evaluation of lesional tissue and blood before and during treatment showed resolution of granulomatous inflammation and normalization of disease biomarkers. CONCLUSION:This case illustrates the promise of JAK inhibition as a strategy to treat recalcitrant sarcoidosis and suggests that further study of JAK inhibitors in sarcoidosis is needed.

| S-EPMC7011417 | biostudies-literature

Tofacitinib for refractory uveitis and scleritis.

Project description:PurposeTo report the successful use of tofacitinib in the treatment of refractory uveitis and scleritis.ObservationsTwo patients, one with scleritis and another with anterior and intermediate uveitis, presented with refractory disease after failure of multiple steroid-sparing therapies. Treatment with tofacitinib led to durable resolution of uveitis and scleritis.Conclusions and importanceTofacitinib is a potential novel treatment option for refractory, noninfectious inflammatory eye disease.

| S-EPMC6288302 | biostudies-literature

Evaluation of tofacitinib in cutaneous sarcoidosis

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-03-30 | GSE169149 | GEO

Tofacitinib for refractory ocular mucous membrane pemphigoid.

Project description:PurposeTo report the successful use of tofacitinib in the treatment of refractory ocular mucous membrane pemphigoid (MMP).ObservationsTwo patients with ocular MMP presented with refractory disease after failure of multiple therapies. Treatment with tofacitinib led to durable control of conjunctival inflammation within 8 weeks and no apparent progression of sub-conjunctival fibrosis. One patient maintained absence of apparent disease activity over 16 months of follow-up. Cessation of tofacitinib in the other patient led to disease relapse which was reversed by re-initiation of therapy.Conclusions and importanceSmall molecule inhibitors of Janus kinases, such as tofacitinib, may offer an effective treatment option for refractory ocular MMP.

| S-EPMC8111584 | biostudies-literature

Tofacitinib in patients with refractory Takayasu's arteritis.

Project description: Not available

| S-EPMC7590403 | biostudies-literature

Systemic Tofacitinib Concentrations in Adult Patients With Atopic Dermatitis Treated With 2% Tofacitinib Ointment and Application to Pediatric Study Planning.

Project description:Atopic dermatitis is a chronic eczematous, pruritic, inflammatory skin condition affecting children and adults. Tofacitinib is a Janus kinase inhibitor. The efficacy, safety, and pharmacokinetics of 2% tofacitinib ointment twice daily have been evaluated in a 4-week phase 2a multisite randomized, double-blind, vehicle-controlled, parallel-group study (NCT02001181) in adult patients with mild to moderate atopic dermatitis and 2% to 20% body surface area (BSA) involvement. Tofacitinib ointment demonstrated significantly greater efficacy versus vehicle for all efficacy end points and had an acceptable safety profile. Predose and postdose pharmacokinetic samples were collected in week 2 and week 4. The objective of this analysis was to assess if predicted mean tofacitinib concentrations with topical application at higher treated BSA across age groups would exceed relevant concentration thresholds based on oral doses of tofacitinib. In this analysis, the pharmacokinetic concentrations were characterized using a linear mixed-effects model. The model was used to predict concentrations for adults with higher (>20%) treatable BSA. Adult concentrations were used to extrapolate concentrations to a pediatric population (2 to 17 years) using allometric principles. The predicted systemic concentrations for 2% tofacitinib ointment in both adult and pediatric populations at treated BSA ≤50% for a mild to moderate atopic dermatitis population did not exceed those reported for the 10th percentile of observed oral tofacitinib 5-mg twice-daily doses in patients with moderate to severe plaque psoriasis. The methodology described will enable analysis and prediction of systemic concentrations for topical agents.

| S-EPMC6590358 | biostudies-literature

Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis.

Project description:There is evidence that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling plays a role in the pathogenesis of sarcoidosis. We treated a patient with cutaneous sarcoidosis with the JAK inhibitor tofacitinib; the patient had not previously had a response to medications and had not received systemic glucocorticoids. This treatment resulted in clinical and histologic remission of her skin disease. Sequencing of RNA and immunohistochemical examination of skin-lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis. (Funded by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research and others.).

| S-EPMC6351852 | biostudies-literature

Fate of lymphocytes after withdrawal of tofacitinib treatment.

Project description:Tofacitinib (Tofa) is an inhibitor of Janus Kinase 3, developed for the treatment of autoimmune diseases and for the prevention of transplant rejection. Due to its selective action on proliferating cells, Tofa can offer a way to block T cell activation, without toxic effects on resting cells. However, few studies have investigated the effects of Tofa on lymphocyte activation in vitro. Our aim was to study the action of Tofa on different lymphocyte subsets after in vitro stimulation and to track the behaviour of treated cells after interruption of the treatment. Peripheral blood lymphocytes were stimulated in vitro with mitogen and treated with two concentrations of Tofa. After a first period in culture, cells were washed and further incubated for an additional time. Lymphocyte subsets, activation phenotype and proliferation were assessed at the different time frames. As expected, Tofa was able to reduce the activation and proliferation of lymphocytes in the first four days of treatment. In addition the drug led to a relative decrease of Natural Killer, B cells and CD8 T cells compared to CD4 T cells. However, treated cells were still viable after the first period in culture and begun to proliferate, strikingly, in a dose dependent manner when the drug was removed from the environment by replacing the culture medium. This novel data does not necessarily predict a similar behaviour in vivo, but can warn about the clinical use of this drug when a discontinuation of treatment with Tofa is considered for any reason.

| S-EPMC3887061 | biostudies-literature

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