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Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review
T Y J Appeldoorn1, T H Oude Munnink1, L M Morsink2
1Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands.
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.
Insights
Ruxolitinib, a JAK/STAT inhibitor, is well-absorbed with hepatic metabolism. Liver and kidney dysfunction necessitate dose adjustments for this important myelofibrosis and polycythemia vera treatment.
Area of Science:
- Pharmacology
- Hematology
Background:
- Ruxolitinib is a Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway inhibitor.
- Used for myelofibrosis, polycythemia vera, and graft-versus-host disease.
- This review focuses on ruxolitinib's pharmacokinetics and pharmacodynamics.
Approach:
- Comprehensive literature search of PubMed, EMBASE, Cochrane Library, and Web of Science.
- Inclusion criteria focused on English-language, human studies of ruxolitinib for hematological diseases.
- Exclusion of non-full-text articles, animal studies, and non-hematological applications.
Key Points:
- Ruxolitinib exhibits high bioavailability (95%) and albumin binding (97%).
- Pharmacokinetics follow a two-compartment model with linear elimination, influenced by hepatic metabolism (CYP3A4) and renal excretion of active metabolites.
- Volume of distribution varies by sex, and hepatic/renal impairment requires dose reduction.
Conclusions:
- Interindividual variability in ruxolitinib pharmacokinetics requires further investigation.
- Optimizing individual ruxolitinib treatment necessitates additional research.
- Model-informed precision dosing shows potential but is not yet standard practice.
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