Tofacitinib - a New Treatment for Rheumatoid Arthritis

Tofacitinib A New Treatment for Rheumatoid Arthritis

Nicholas Fifelski

Liberty University

Introduction

Tofacitinib is a drug that has recently been approved by the Food and Drug Administration (FDA). The clinical hopes of the drug will be to treat Rheumatoid arthritis; the drug was first discovered in 1994 by Pfizer, but was not approved for clinical uses until 2012.  This novel drug works as a Janus kinase inhibitor, which in turn reduces proinflammatory cytokine production, activation, and expression (OShea, 2004). The Janus kinase (Jak) pathway is used by cytokines to facilitate intracellular signaling; Jaks can be found in the cytosol inner membrane portion of cytokine receptors on a proline rich region. Once cytokine receptors are bound, the Jaks phosphorylate each other, and proceed to phosphorylate a tyrosine region for the signal transducers and activators of transcription pathway (STATs). STATs are cytoplasmic transcription factors that have src homology 2 domains, that when phosphorylated, causes STATs to be translocated into the nucleus where it induces transcription of genes involved in inflammatory response. An over expression of cytokines, and proinflammatory production are a “trademark” sign of specific autoimmune diseases such as rheumatoid arthritis, and psoriasis. Thus, inhibitors of the Jak pathway show promising qualities that may be able to reduce the inflammation associated with autoimmune diseases (Dowty, Lin, Ryder, Wang, Walker, Vaz, Chan, Krishnaswami, Prakash, 2013.)

Chemistry/Structure of the drug

Tofacitinib is a pyrrolopyrimidine with a chemical formula of C16H20N6O1; Tofacitinib works by binding to Jak 3, which keeps it from transferring a phosphate group to signal and transducer of transcription.  The structure of tofacitinib, and its metabolites are shown in figures 1, and 2 (Dowty, Lin, Ryder, Wang, Walker, Vaz, Chan, Krishnaswami, Prakash, 2013.).

Figure 1. The structure of tofacitinib, a pyrrolopyrimidine.

[pic 1]

Adverse effects

The most common adverse reactions (ARs) include hypertension, headaches, and upper respiratory tract infection due depressed immune capabilities. The drug is also believed to be associated with serious opportunistic infections such as tuberculosis (TB); tofacitinib is thought to promote cancer, and lymphoma.  The product labeling warns against cancer, and lymphomas, but most studies show little to no association between taking tofacitinib, and cancer or lymphoma. Tofacitinib has been associated with gastrointestinal perforation, low blood and hemoglobin count.  Moreover, it has also been shown to lower leukocytes which leads to a higher risk of infection.  The FDA ordered that long term studies be set up, so that tofacitinib can be monitored for long term side effects in regards to heart disease, cancer, and lymphoma; moreover, tofacitinib has also shown to have feticidal and teratogenic effects in animal models, and therefore, should not be used by women who are pregnant.  

Mechanism of action pharmacokinetics/Drug interactions

As previously stated Tofacitinib is a pyrrolopyrimidine that inhibits Jak 1/3 from phosphorylating Signal transducer or activator of transcription (STAT) pathway, which normally leads to cytokine activation, hematopoiesis, and inflammation.  Cytokine receptors lie on the membranes of tissue cell, and   Jak 3 is associated with the Box 1 and 2 proline regions on the cytokine receptors. The paired polypeptide cytokine receptors when bound by cytokine/ligands in turn activate Jak 3 by promoting self-phosphorylation within the Jak complex, and this allows the Jak complex to phosphorylate the STATS pathway which travels to the nucleus and initiates transcription (O’Shea, & Schindler, 2004, 2007).

The half-life of tofacitinib has been calculated to be approximately 3.2 hours, and max concentration has been shown to be around the 1 hour mark after oral administration. Tofacitinib is thought to be rapidly absorbed within the body; the 24-hour recovery rate for tofacitinib is 78.5% with roughly 77% being in the urine, and 1.5% being in the stool. A study showed that at 192 hours 93% of the tofacitinib was recovered via stool and urine. Tofacitinib consists of 12 metabolites, with 5 of them having definitive structures (Metabolites 1,2,4,9, Figure 1), however, the parent drug consists of 70% of all drug related material in the serum. Therefore, the oral bioavailability of tofacitinib is thought to 74% with a total plasma clearance of 413ml/min. (Gupta et al., 2011) The clearance of tofacitinib is also believed to be 30% renal, and 70% hepatic, the renal and hepatic clearance have been calculated to be roughly 124 ml/min; in one study the glomerular filtration rate (GFR) has calculated to be 76 ml/min (Dowty, Lin, Ryder, Wang, Walker, Vaz, Chan, Krishnaswami, Prakash, 2013.).

A study involving six health males was conducted, and the results show that tofacitinib is primarily metabolized in the liver by cytochrome P450 (70%), and thus inhibitors of cytochrome P450 such as, anticonvulsants, anti-depressants, and proton pump inhibitors will increase the serum concentration of tofacitinib. Namely, ketoconazole, and fluconazole have been shown to dramatically increase serum tofacitinib levels (104%). Whereas, cytochrome P450 inducers such as, rifampicin (bactericidal) artemisinin (by malaria) carbamazepine (anticonvulsant, mood), norethisterone (contraceptive), prednisone (corticosteroid), and  aspirin have been shown to decrease tofacitinib serum levels, and therefore these drugs should be avoided or taken in very small amount when taking tofacitinib. It should be noted that rifampicin has been shown to decrease serum tofacitinib by 84%. Furthermore, tofacitinib should not be taken with any other forms of immunosuppressant drugs; one should be immunized, but not given live vaccines before or during tofacitinib administration.  Cytochrome P450 is found mostly in the liver, and the small intestines, which is where the oxidation of Tofacitinib takes place. The primary transformation of tofacitinib was shown to be oxidation of the pyrrolopyrimidine ring, oxidation of the piperdine ring, piperdine ring side chain oxidation, and N-demethylation, which is evidence that tofacitinib is metabolized by cytochrome P450. Out of the cytochrome P450s, CYP3A4 is thought to be the most active, followed by CYP2C19 (Dowty, Lin, Ryder, Wang, Walker, Vaz, Chan, Krishnaswami, Prakash, 2013).