Tofacitinib

Absorption

74% oral absorption (absolute bioavailability), with peak plasma concentrations (T max) achieved in 0.5-1 hour.
Administration with fatty meals does not alter AUC but reduces Cmax by 32%.

Toxicity

Minimum lethal dose in rat: 500 mg/kg. Maximum asymptomatic dose in non human primate: 40 mg/kg.
Lymphatic, immune system, bone marrow and erythroid cell toxicity was seen in animal studies involving rate and monkeys. Doses used in these studies ranged from 1mg/kg/day to 10mg/kg/day, over a duration of 6 weeks to 6 months. Lymphopenia, neutropenia, and anemia is seen in human subjects and may call for an interruption or discontinuation of therapy if severe.
Reduced female fertility in rats was seen at exposures 17 times the maximum recommended human dose. Fertility may be impaired in human females and harm may be caused to unborn child. Carcinogenic potential is seen, however evidence for dose dependency is lacking.
Because the janus kinase pathway plays a role in stimulating the production of red blood cells and is involved in immune cell function, inhibition of this pathway leads to increased risk of anemia, neutropenia, lymphopenia, cancer and infection.
Lymphopenia, neutropenia, and anemia in human subjects may call for an interruption or discontinuation of therapy if severe.
Role of JAK inhibition in the development of gastrointestinal perforation is not known.

Description

Tofacitinib (trade names Xeljanz and Jakvinus; Pfizer) and ruxolitinib (Jakafi and Jakavi; Incyte Pharmaceuticals and Novartis) are Janus kinase (JAK) inhibitors that are used to treat rheumatoid arthritis and myelofibrosis, respectively. Tofacitinib (structure 1) was the first to be developed; it was the outgrowth of research performed at the National Institutes of Health by John O''Shea and co-workers.
Ruxolitinib (structure 2) did not come along until about 5 years ago. It may also be useful for treating other disease such as lymphoma, pancreatic cancer, and polycythemia vera.
Both drugs are now being looked at to treat a very widespread but much less serious condition: hair loss. A Columbia University team led by Angela M. Christiano observed that administering the drugs orally to mice promoted hair growth. The downside was that the animals'' immune systems were compromised, so the researchers applied the drugs topically and obtained similar hair growth results.
It turns out that JAK inhibition is the key to this effect as it is for disease treatment. The drugs inhibit a kinase pathway in dormant hair follicle cells that causes the cells to transcribe DNA. Inhibiting the pathway "wakes up" the cells, and hair growth ensues.

Description

In November 2012, the US FDA approved tofacitinib (also referred to as CP-690550) for the treatment of adult patients with moderate to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate. Tofacitinib is the first small molecule kinase inhibitor approved for the treatment of RA. Tofacitinib is an inhibitor of the four subtypes of Janus kinase (JAK): JAK1, JAK2, JAK3, and Tyk2. The JAKs are intracellular, nonreceptor tyrosine kinases that play important roles in the signal transduction pathway of many cytokines (e.g., interleukins 2, 4, 7, 9, 15, and 21) and are involved in the propagation of inflammation in RA. Tofacitinib acts by inhibiting the phosphorylation and activation of signal transducers and activators of transcription (STATs), thereby suppressing the production of inflammatory mediators in joint tissue. At the enzyme level, tofacitinib inhibits JAKs 1, 2, 3, and Tyk2 with IC_50s of 3.2, 4.1, 1.6, and 34 nM, respectively. At the cellular level, tofacitinib inhibits the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC_50s of 406, 56, and 1377 nM, respectively.

Chemical properties

Light Pink to Pale Orange Solid

Originator

Pfizer (United States)

Characteristics

Class: non-receptor tyrosine kinase
Treatment: RA, PA, JIA, UC
Oral bioavailability = 74%
Elimination half-life = 3.2 h
Protein binding = 40%

The Uses of Tofacitinib

CP-690550 is a pyrrolo[2,3-d]pyrimidine derivative, as Janus kinase inhibitor for treatment of rheumatoid arthritis

Indications

Tofacitinib is indicated for the treatment of adult patients with moderately-to-severely active rheumatoid arthritis (RA), active psoriatic arthritis, active ankylosing spondylitis, or moderately-to-severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers. It is also indicated as an oral solution in patients ≥2 years of age for the treatment of polyarticular course juvenile idiopathic arthritis who have had an inadequate response or intolerance to one or more TNF blockers.
Tofacitinib is not recommended to be used in combination with other biologic disease-modifying anti-rheumatic drugs (DMARDs) or potent immunosuppressive agents such as azathioprine or cyclosporine.

Background

Tofacitinib is an inhibitor of Janus kinases, a group of intracellular enzymes involved in signalling pathways that affect hematopoiesis and immune cell function. It is approved by the FDA for treatment of moderate to severe rheumatoid arthritis that responds inadequately to methotrexate or in those who are intolerant to methotrexate. Besides rheumatoid arthritis, tofacitinib has also been studied in clinical trials for the prevention of organ transplant rejection, and is currently under investigation for the treatment of psoriasis. Known adverse effects include nausea and headache as well as more serious immunologic and hematological adverse effects. Tofacitinib is marketed under the brand name Xeljanz by Pfizer.

Definition

ChEBI: A pyrrolopyrimidine that is pyrrolo[2,3-d]pyrimidine substituted at position 4 by an N-methyl,N-(1-cyanoacetyl-4-methylpiperidin-3-yl)amino moiety. Used as its citrate salt to treat moderately to severely ctive rheumatoid arthritis.

Indications

The JAK family includes four isoforms, JAK1, JAK2, JAK3, and tyrosine kinase (TYK2). Ruxolitinib (Jakafi(R), Incyte Corp.) was the first approved JAK inhibitor, which inhibits both JAK1 and JAK2, used for the treatment of different types of myelofibrosis. Tofacitinib (Xeljanz(R), Pfizer) was approved by FDA as a JAK3-selective inhibitor for the treatment of rheumatoid arthritis and is one of the only two FDA-approved kinase inhibitors for non-oncological indications.

brand name

Xeljanz

Pharmacokinetics

Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway.
In placebo controlled trials of rheumatoid arthritis patients receiving 5mg or 10mg of tofacitinib twice daily, higher ACR20 responses were observed within 2 weeks in some patients (with ACR20 being defined as a minimum 20% reduction in joint pain or tenderness and 20% reduction in arthritis pain, patient disability, inflammatory markers, or global assessments of arthritis by patients or by doctors, according to the American College of Rheumatology (ACR) response criteria list), and improvements in physical functioning greater than placebo were also noted.
Common known adverse effects of tofacitinib include headaches, diarrhea, nausea, nasopharyngitis and upper respiratory tract infection. More serious immunologic and hematological adverse effects have also been noted resulting in lymphopenia, neutropenia, anemia, and increased risk of cancer and infection.
Before initiations of tofacitinib patients should be tested for latent infections of tuberculosis, and should be closely monitored for signs and symptoms of infection (fungal, viral, bacterial, or mycobacterial) during therapy. Therapy is not to be started in the presence of active infection, systemic or localized, and is to be interrupted if a serious infection occurs.
Tofacitinib has been associated with an increased risk of lymphomas, such as Epstein-Barr virus associated lymphomas, and other malignancies (including lung, breast, gastric, and colorectal cancers). It is recommended to monitor lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids.
Tofacitinib use is associated with a rapid decrease in C-reactive protein (CRP), dose dependent decreases in natural killer cells, and dose dependent increases in B cells. Depression in C-reactive protein levels continue after 2 weeks of tofacitinib discontinuation and suggest that pharmacodynamic activity last longer than pharmacokinetic half life.

Pharmacokinetics

Tofacitinib has good solubility (>4 mg/mL in water for the crystalline citrate salt), which contributes to its excellent oral bioavailability (74%) in healthy volunteers. However, tofacitinib exhibits relatively short elimination half-life of 3.2 hours, and its protein binding is very low (approximately 40%, predominantly to albumin). Tofacitinib undergoes major hepatic clearance (70% of total clearance) and minor renal clearance (30%). The metabolism of tofacitinib proceeds primarily in the liver by CYP3A4 (major) and CYP2C19 (minor), resulting in oxidation of the pyrrolopyrimidine and piperidine rings, oxidation of the piperidine ring side-chain, N-demethylation, and glucuronidation. As opposed to the longer half-life of biologics, small-molecule JAK inhibitors such as tofacitinib typically display much shorter half-lives with once or twice-daily dosing regimens, which may be inconvenient to some patients. However, the shorter half-life ensures faster recovery to the full ability to fight infections which may occur with any immune suppressing medication.

Clinical Use

Tofacitinib was approved for treating rheumatoid arthritis in 2012, joint pain and swelling, psoriatic arthritis in 2017, and ulcerative colitis in 2018. However, severe side effects observed during clinical studies prevented the FDA from approving more efficacious doses for the treatment of rheumatoid arthritis (RA). Tofacitinib also carries a black box warning for an increased risk of pulmonary embolism and death associated with the 10 mg BID dose.

Synthesis

Commercially available aminopyridine 171 was reacted with dimethyl dicarbonate in the presence of potassium t-butoxide to give the methyl carbamate 172 in 87% yield. Hydrogenation of this carbamate 172 in the presence of 20 wt% of 5% Rh/C (JM type C101023-5) in acetic acid followed by reductive amination with benzaldehyde and sodium triacetoxy borohydride furnished the cis-benzyl protected piperidine 173 in 73% yield. Reduction of the methyl carbamate within 173 with lithium aluminum hydride (LAH) in THF gave the corresponding methyl amino piperidine which was isolated as the dihydrochloride salt 174 in 87% yield. Enantiomeric resolution of the methyl amino piperidine was achieved by freebasing the di-hydrochloride salt 174 with sodium hydroxide and then conversion to the di-toluol-L-tartaric acid salt followed by crystallization to give 175 in 42% yield and 98.6% ee. The enantioenriched tartrate salt 175 was then directly reacted with dichloride 176 (obtained from reaction of commercial 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (178) with phosphorous oxychloride) in the presence of potassium carbonate in water to give the coupled product 177 in essentially quantitative yield. Hydrogenation of intermediate 177 with DeGussa?ˉs catalyst triggered concomitant debenzylation and chloride removal, and this was followed by installation of the cyanoacetate group and subsequent treatment with citric acid to provide tofacitinib citrate (XXVII) in 90% yield.

Metabolism

Metabolized in the liver by CYP3A4 and CYP2C19. Metabolites produced are inactive.

References

1) Jiang et al. (2008), Examining the chirality, confirmation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitril (CP-690,550); J. Mol. Chem., 51 8012 2) Cutolo and Meroni (2013), Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis; J. Inflamm. Res., 6 129 3) Martina et al. (2016), Inhibition of JAK3 and PKC via Immunosuppressive Drugs Tofacitinib and Sotrastaurin Inhibits Proliferation of Human B Lymphocytes In Vitro; Transplant. Proc., 48 3046 4) Moisan et al. (2015), White-to-brown metabolic conversion of human adipocytes by JAK inhibition; Nat. Cell Biol., 17 57 5) Dowty et al. (2014), Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis; J. Pharmacol. Exp. Ther., 348 165