Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review

Abstract

Background and Objective Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to treat myelofibrosis, polycythemia vera and steroid-refractory graft-versus-host disease in the setting of allogeneic stem-cell transplantation. This review describes the pharmacokinetics and pharmacodynamics of ruxolitinib. Methods Pubmed, EMBASE, Cochrane Library and web of Science were searched from the time of database inception to march 15, 2021 and was repeated on November 16, 2021. Articles not written in English, animal or in vitro studies, letters to the editor, case reports, where ruxolitinib was not used for hematological diseases or not available as full text were excluded. Results Ruxolitinib is well absorbed, has 95% bio-availability, and is bound to albumin for 97%. Ruxolitinib pharmacokinetics can be described with a two-compartment model and linear elimination. Volume of distribution differs between men and women, likely related to bodyweight differences. Metabolism is mainly hepatic via CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. The major metabolites of ruxolitinib are pharmacologically active. The main route of elimination of ruxolitinib metabolites is renal. Liver and renal dysfunction affect some of the pharmacokinetic variables and require dose reductions. Model-informed precision dosing might be a way to further optimize and individualize ruxolitinib treatment, but is not yet advised for routine care due to lack of information on target concentrations. Conclusion Further research is needed to explain the interindividual variability of the ruxolitinib pharmacokinetic variables and to optimize individual treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01225-7.

Electrochemical Behavior of Janus Kinase Inhibitor Ruxolitinib at a Taurine-Electropolymerized Carbon Paste Electrode: Insights into Sensing Mechanisms

“…Ruxolitinib is the predominant entity in humans, representing approximately 60% of the circulating drug-related material. Its excretion is 22% in feces and 74% in urine. , …”

“…Its excretion is 22% in feces and 74% in urine. 4,52 In light of the above information, it can be thought that the electrochemical oxidation occurs in the pyrrolopyrimidine ring, which is the main part of the structure of RXL. 53 Therefore, it was stated that the oxidation reaction took place as 2H + −2e − on the poly(taurine)-CP electrode surface.…”

“…Its primary mode of action involves the inhibition of the JAK-mediated phosphorylation of STAT proteins. Consequently, ruxolitinib disrupts cell division and promotes apoptosis, thereby exerting its therapeutic effects. − RXL received its first approval from the US Food and Drug Administration (FDA) in 2011 for the treatment of myelofibrosis. Subsequent approvals followed in 2014 for polycythemia vera and in 2019 for steroid-refractory graft-versus-host disease.…”

Idasanutlin and navitoclax induce synergistic apoptotic cell death in T-cell acute lymphoblastic leukemia

“…To directly assess the activity of JAK2 inhibitors, we treated the T-ALL PDX lines with ruxolitinib (a competitive inhibitor of the JAK1 and JAK2 kinases) alone, idasanutlin alone, or the combination. At clinically relevant doses [ 39 , 40 ], ruxolitinib treatment induced a statistically significant, but modest, growth suppression in all T-ALL PDX lines, which was potentiated by the addition of idasanutlin (Fig. S 4A–E ).…”

JAK Inhibitors as Potential Therapeutic Strategy for the Dilemma of Psoriasis Concurrent with Dermatomyositis in the SARS-CoV-2 Era

“…Based on our data above, the medication targeting type II interferon-mediated signaling pathway could be a potential solution for the psoriasis concurrent with dermatomyositis dilemma. Type II interferon-mediated signaling pathway is controlled by Janus Kinase (JAK) 1 and JAK2 which several JAK inhibitors targeting this pathway including tofacitinib, 16 ruxolitinib, 17 baricitinib, 16 abrocitinib 18 and etc. There were several JAK inhibitors proved effective in the treatment of dermatomyositis.…”