ruxolitinib   

GtoPdb Ligand ID: 5688

Synonyms: (R)-ruxolitinib | INC424 | INCB 18424 | INCB018424 | Jakafi® | Jakavi®
ruxolitinib is an approved drug (FDA (2011), EMA (2012))
Compound class: Synthetic organic
Comment: Ruxolitinib is a Type-1 kinase inhibitor and was first approved by the US FDA in 2011. Ruxolitinib has high potency against Janus kinases 1 and 2 (JAK1, JAK2), as well as against the related family member, tyrosine kinase 2 (TYK2) [3]. Inhibitory activity against JAK3 is only slightly reduced compared to the other three family kinases.
Marketed formulations may contain ruxolitinib phosphate (PubChem CID 25127112).
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2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 4
Hydrogen bond donors 1
Rotatable bonds 4
Topological polar surface area 83.18
Molecular weight 306.16
XLogP 2.7
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES N#CCC(n1ncc(c1)c1ncnc2c1cc[nH]2)C1CCCC1
Isomeric SMILES N#CC[C@@H](n1ncc(c1)c1ncnc2c1cc[nH]2)C1CCCC1
InChI InChI=1S/C17H18N6/c18-7-5-15(12-3-1-2-4-12)23-10-13(9-22-23)16-14-6-8-19-17(14)21-11-20-16/h6,8-12,15H,1-5H2,(H,19,20,21)/t15-/m1/s1
InChI Key HFNKQEVNSGCOJV-OAHLLOKOSA-N
No information available.
Summary of Clinical Use
Used to treat intermediate or high-risk myelofibrosis including including primary myelofibrosis, post-polycythemia vera (post-PV) myelofibrosis and post-essential thrombocythemia (post-ET) myelofibrosis.
In 2014 ruxolitinib was approved for use as a treatment for polycythemia vera, a chronic type of bone marrow disease.
In May 2019, the FDA approved ruxolitinib as a treatment for steroid-refractory acute graft-versus-host disease (GvHD) in patients ≥12 years old.

Interesting results from small trials in patients with alopecia areata suggest that by killing the immune cells responsible for hair loss in this disease, ruxolitinib can promote hair re-growth [4,7].
Mechanism Of Action and Pharmacodynamic Effects
Ruxolitinib is a kinase inhibitor that is selective for the Janus associated kinases (JAK) 1 and 2. These kinases mediate cytokine and growth factor signalling which in turn effect immune function and hematopoiesis. The signalling process involves signal transducers and transcription activators (STATs) which modulate gene expression. Patients with myelofibrosis have abnormal JAK1 and JAK2 activity thus ruxolitinib works to regulate this. The mechanism of dysregulation is believed to include high levels of circulating cytokines that activate the JAK-STAT pathway, gain-of-function mutations such as JAK2V617F, and silencing of negative regulatory mechanisms for example. Administration of ruxolitinib causes a dose-dependent decrease in levels of phosphorylated STAT which is used as a marker for JAK activity. Pharmacodynamic resistance has not been reported.
Pharmacokinetics
Absorption/Distribution
Ruxolitinib is rapidly absorbed, with maximal plasma concentration achieved approximately 1 hour post-dose and can be administered with or without food. Bioavailability is >95%. Approximately 97% is bound to plasma proteins, mainly albumin. Autoradiographic study in rats has shown that ruxolitinib does not penetrate the blood-brain barrier.
Biotransformation/Metabolism
Ruxolitinib is metabolized by CYP3A4, generating less potent active metabolites.
Elimination
Ruxolitinib is eliminated via feces (22%, <1% as unchanged drug) and urine (74%, <1% as unchanged drug).
Population pharmacokinetics
The pharmacokinetics of ruxolitinib are not significantly affected by age, gender or race. The pharmacokinetics have not been evaluated in children
Organ function impairment
A dose reduction of approximately 50% is recommended for patients with hepatic impairment. Exposure to ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites tended to increase with increasing severity of renal impairment, and were most markedly increased in the subjects with severe renal impairment. It is unknown whether the increased metabolite exposure is of safety concern. A dose modification is recommended in patients with severe renal impairment and end-stage renal disease. In a study of QT in healthy subjects, there was no evidence that a single dose of ruxolitinib increased QT/QTc, indicating that ruxolitinib has no effect on cardiac repolarisation.
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