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Upadacitinib

 

Upadacitinib, a Janus kinase (JAK) inhibitor medication for the treatment of moderately to severely active rheumatoid arthritis in adults.

 

It is an oral, reversible Janus kinase inhibitor.

 

 

The Janus kinases (JAKs) are a family of cytoplasmic tyrosine kinases whose function is to transduce cytokine-mediated signals via the JAK-STAT pathway. 

 

 

Has activity for JAK1 over JAK2, JAK3 and tyrosine kinase2’.

 

 

There are four JAK subtypes as above, each of which has overlapping receptor responsibilities. 

 

 

Inhibitors of this enzyme family have shown efficacy in treating certain inflammatory and autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. 

 

 

It works by blocking the action of Janus kinases.

 

 

Brand name Rinvoqis.

 

 

It is used in patients where methotrexate  did not work well or could not be tolerated.

 

 

It is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs).

 

 

Pregnancy category US: N (Not classified yet).

 

 

Routes of administration-orally.

 

 

Protein binding 52%.

 

 

Metabolism Hepatic (CYP3A major, CYP2D6 minor).

 

 

Elimination half-life 9–14 hours.

 

 

Excretion-Mainly unchanged in feces (38%) and urine (24%).

 

 

Side effects include:  upper respiratory tract infections, nausea, cough, and fever.

 

 

Janus kinases are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.

 

 

It may be used as monotherapy or in combination with methotrexate.

 

 

It is contraindicated in people with active tuberculosis and other severe infections, severe liver impairment and during pregnancy.

 

 

Its use with other Janus kinase inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporin is not recommended.

 

 

Strong  inhibitor drugs of  the liver enzyme CYP3A4, such as ketoconazole, itraconazole or clarithromycin, increase upadacitinib concentrations in the body. 

 

 

Upadacitinib seems to be a weak inducer of CYP3A4, as it lowers concentrations of other substrates of this enzyme?

 

 

Common side effects of upadacitinib: upper respiratory tract infections such as common cold and sinus infections, nausea, cough, fever, and increased liver enzymes. 

 

 

Serious side effects include life threatening infections, including life-pneumonia, cellulitis, tuberculosis, as well as shingles and other herpes infections.

 

 

The first generation of these drugs, tofacitinib and ruxolitinib, lack subtype selectivity: affecting JAK1/JAK3 and JAK1/JAK2 respectively.

 

 

Upadacitinib is a second generation Janus kinase inhibitor that is selective for the JAK1 subtype of this enzyme over the JAK2 , 74-fold, JAK3 at 58-fold and tyrosine kinase 2 subtypes.

 

 

It reaches highest concentrations in the blood plasma two to four hours after ingestion.

 

 

It reaches steady-state conditions after four days and accumulation is minimal. 

 

 

52% of the substance are bound to plasma proteins. 

 

 

 Metabolized by CYP3A4, and possibly to a minor extent by CYP2D6. 

 

 

The most important pathway consists of oxidation to a carboxylic acid and subsequent glucuronidation, yielding a metabolite called M4. However, 

 

 

79% of the drug are circulating in form of upadacitinib itself, and only 13% as M4, metabolite.

 

 

It  is excreted mainly as the original substance, of which 38% are found in the feces and 24% in the urine. 

 

 

The mean terminal half-life is 9 to 14 hours.

 

 

Inhibition of CYP3A by ketoconazole increases total AUC, indicating the importance of this metabolic route.

 

 

In a study of 276 rheumatoid arthritis who had previously failed  anti–tumor necrosis factor (TNF) therapy and were currently on a stable dose of methotrexate: response rates were significantly higher in those receiving upadacitinib versus in those receiving placebo alone, 36–42% and 22– 26%, respectively.

 

 

In a study of 300 rheumatoid arthritis patients with an  inadequate response to methotrexate: response rates were significantly higher in those receiving upadacitinib versus in those receiving placebo alone: 62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively. than with placebo (46%).

 

 

Adverse events include: headache, nausea, and infection.

 

 

Improvement in symptoms are  rapid, with significant changes in disease scores by week 2. 

 

 

Adverse events are mild with infection being the most serious. 

 

 

 

In SELECT-COMPARE 1629 patients with moderate to severe rheumatoid arthritis and inadequate response to methotrexate were randomized (2:2:1) to once-daily upadacitinib 15mg, placebo, or adalimumab 40mg, on stable background methotrexate. 

 

 

Upadacitinib was superior to adalimumab, achieving  low disease activity or remission.

 

 

Radiographic progression was less and observed in fewer patients receiving upadacitinib versus placebo.

 

 

Upadactinib is superior to abatacept in the achievement of remission in patients refractory to biologic DMRDS.

 

 

In 220 patients with moderately to severely active Crohn’s disease:significant improvement in symptoms compared to placebo. 

 

The percentage of patients  with psoriatic arthritis with a clinical response was significantly higher with who Upadacitinib than with placebo.

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