Ruxolitinib

Inhibitor of Janus kinase (tyrosine kinase), which is used for the treatment of primary myelofibrosis, polycythemia vera and post-polycythemia vera myelofibrosis. The molecular formula is: C17H18N6.

Inhibition of Janus kinases 1 and 2 (see Janus kinases).

Ruxolitinib is a selective inhibitor of JAK1 and JAK2, which inhibits cytokine-induced phosphorylation of STAT3 in whole blood. MF and PV are diseases in which there is a dysregulation of the JAK1 and JAK2 signaling pathways.

Several mechanisms come into question here:

• High levels of circulating cytokines leading to activation of JAK-STAT signaling pathways (see JAK inhibitors for exact mechanism).
• Gain-of-function mutations such as JAK2V617F (MF patients exhibit JAK dysregulation regardless of mutation status, in PV patients activating mutations in JAK2 are present in more than 95% of cases)
• Elimination of negative control mechanisms
• These mechanisms lead to an overactivation of the JAK-STAT signaling cascade and consequently to a hyperproliferation of hematopoietic progenitor cells, which is to be prevented by ruxolitinib.

Absorption: According to the Biopharmaceutical Classification System (BCS), ruxolitinib is a class I molecule with a high permeation capacity and high solubility.

Ruxolitinib is rapidly absorbed after oral administration and reaches its maximum plasma concentration (cmax) approximately 1 hour after ingestion. The mean cmax and AUC increase proportionally with single doses of 5 to 200 mg. The intake of high-fat meals has no clinically relevant influence on the pharmacokinetics of ruxolitinib (cmax reduction by 24%, while the AUC remains almost unchanged).

Distribution: The mean volume of distribution at steady state in MF and PV patients is approximately 75 L. Ruxolitinib is approximately 97% bound to plasma proteins, especially albumin, at clinically relevant concentrations.

Metabolism (biotransformation): Ruxolitinib is more than 50% metabolized via CYP3A4 with additional involvement of CYP2C9. About 60% of the active substance is present in the bloodstream as starting substance. There are 2 main active metabolites present in plasma, corresponding to 25% and 11% of the AUC of the parent compound (possessing about 20 to 50% of the pharmacological activity of the parent compound in terms of JAKs).

Elimination: Ruxolitinib is eliminated predominantly by metabolism, with the majority excreted renally. The mean elimination half-life is approximately 3 hours.

Special patient populations

Gender and origin do not appear to have any pharmacokinetic influence. Dose adjustment is recommended for patients with severe renal impairment and end-stage renal disease, as the AUC of the metabolites increases. In patients with hepatic impairment, a dose reduction of approximately 50% is recommended, as the mean AUC for ruxolitinib is increased in these patients.

Ruxolitinib is available as a tablet in doses of 5, 10, 15 and 20 mg.

Ruxolitinib is available on the market as a cream in a 1.5% concentration. Indication: Atopic dermatitis.

The JAK inhibitor ruxolitinib (^Jakavi®) is primarily indicated for the treatment of myeloproliferative neoplasms. These include myelofibrosis (MF) and polycythaemia vera (PV).

Myelofibrosis: Ruxolitinib is used for disease-related splenomegaly or symptoms in adults with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.

Polycythaemia vera: Ruxolitinib is also indicated for the treatment of adults with polycythaemia vera who are resistant or intolerant to hydroxycarbamide.

Since May 2023, the active substance has also been available on the German market in the form of a cream (^Opzelura®) to support repigmentation in non-segmental vitiligo.

Its use in alopecia areata is experimental.

A 1.5% ruxolitinib cream has been used experimentally with good clinical success in atopic dermatitis (Kim BS et al. 2020; Gong X et al. 2021).

Dizziness and headaches. Thrombocytopenia, leukopenia and haemorrhage have also been described in the Phase III studies. Further increase in infections, hypertension.

^Jakafi®, ^Jakavi®

^Opzelura® cream

1. Falto-Aizpurua L et al (2014) Emerging treatments in alopecia. Expert Opin Emerg Drugs 19:545-556
2. Gong X et al (2021) Pharmacokinetics of ruxolitinib in patients with atopic dermatitis treated with ruxolitinib cream: data from phase II and III studies. Am J Clin Dermatol 22:555-566.
3. Mesa R et al.(2016) The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF). Br J Haematol. doi: 10.1111/bjh.14382.
4. Kettle JG et al.(2016) Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1. Expert Opin Ther Pat 7:1-17.
5. Kettle JG et al.(2016) Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 2. Expert Opin Ther Pat 4:1-17.
6. Kim BS et al. (2020) Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J Allergy Clin Immunol 145:572-582.
7. Pieri L et al (2014) Ruxolitinib-Induced Reversal of Alopecia Universalis in a Patient with Essential Thrombocythemia. Am J Hematol 2014 doi: 10.1002/ajh.23871.
8. Xing L et al (2014) Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 20:1043-1049