Ruxolitinib

Abstract

Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of Janus kinase (JAK) 1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis (MF) by the US Food and Drug Administration (FDA) in 2011 and by the European Medicines Agency (EMA) in 2012, followed by the approval for the treatment of hydroxyurea (HU)-resistant or -intolerant polycythemia vera (PV) in 2014. Both MF and PV are myeloproliferative neoplasms (MPNs) which are characterized by the aberrant activation of the JAK-STAT pathway. Clinically, MF features bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. PV is characterized by the overproduction of primarily red blood cells (RBC), risk of thrombotic complications, and development of secondary MF. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of MF patients and may also have a favorable effect on survival. In PV, ruxolitinib effectively controls the hematocrit and reduces splenomegaly. Since recently, ruxolitinib is also under investigation for the treatment of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Toxicities of ruxolitinib include myelosuppression, which results in dose-limiting thrombocytopenia and anemia, and viral reactivations. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently under investigation for MPNs or other immuno-inflammatory diseases.

IFN-independent G0 arrest and SAMHD1 activation following TLR4 activation in macrophages

“…TLR4 activation stimulates production of interferons (IFN). In order to understand if IFN plays role in SAMHD1 activation/dephosphorylation after TLR4 activation as recently published 16, 22 , we used the JAK1/2 inhibitor Ruxolitinib (RUXO) that inhibits IFN signalling (Fig.1C) 23 . The inhibitor of IFN signalling could not restore infection and failed to reverse SAMHD1 phosphorylation at T592, suggesting that regulation of SAMHD1 phosphorylation is largely independent of IFN (Fig.1F).…”

Repurposing anticancer drugs for the management of COVID-19

“…Ruxolitinib is a potent orally bioavailable Janus kinase (JAK) 1 and JAK2 inhibitor indicated for various myeloproliferative malignancies including myelofibrosis and polycythemia vera ( Ajayi et al 2018 ; Vannucchi et al 2015 ; Verstovsek et al 2012 ). These neoplasms, alongside with the acute myeloid leukemia, are known by their aberrant activation of the JAK-STAT signaling ( Venugopal et al 2020 ).…”

Safety of Janus Kinase Inhibitors in Older Patients: A Focus on the Thromboembolic Risk

“…Tofacitinib is primarily metabolized in the liver through CYP3A4 so requires dose adjustments when coadministered with CYP3A4 inhibitors [8]. On the other hand, the toxicity of ruxolitinib may increase if coadministered with potent CYP3A4 inhibitors [9]. In contrast, baricitinib is a first-generation jakinib that is metabolized not via the CYP system [2] but via the kidney.…”