Article ; Online: Multiple administrations of fluconazole increase plasma exposure to ruxolitinib in healthy adult subjects.
Cancer chemotherapy and pharmacology
2019 Volume 84, Issue 4, Page(s) 749–757
Abstract: Purpose: Ruxolitinib is metabolized by cytochrome P450 (CYP)3A4 and CYP2C9. Dual inhibitors of these enzymes (like fluconazole) lead to increased ruxolitinib exposure relative to a single pathway inhibition of CYP3A4 or CYP2C9. The magnitude of this ... ...
| Abstract | Purpose: Ruxolitinib is metabolized by cytochrome P450 (CYP)3A4 and CYP2C9. Dual inhibitors of these enzymes (like fluconazole) lead to increased ruxolitinib exposure relative to a single pathway inhibition of CYP3A4 or CYP2C9. The magnitude of this interaction, previously assessed via physiologically based pharmacokinetic (PBPK) models, was confirmed in an open-label, phase 1 study in healthy subjects. Methods: The effect of multiple doses (200 mg) of fluconazole on single-dose (10 mg) PK of ruxolitinib was investigated including evaluation of the safety and tolerability. The PK parameters of ruxolitinib alone (reference) were compared to those of ruxolitinib combined with fluconazole (test). The point estimate and corresponding two-sided 90% confidence interval for the difference between means of test and reference parameters were determined. Results: All enrolled subjects (N = 15) completed the study. When coadministered with fluconazole, geometric means of ruxolitinib PK parameters C Conclusions: Coadministration of ruxolitinib with fluconazole significantly increased ruxolitinib systemic exposure; however, no AEs were attributed to ruxolitinib. Concomitant use of ruxolitinib with fluconazole (dose ≤ 200 mg) may require dose reduction/modification of ruxolitinib. |
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| MeSH term(s) | Adult ; Cytochrome P-450 CYP2C9/metabolism ; Cytochrome P-450 CYP3A/metabolism ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Interactions ; Enzyme Inhibitors/pharmacokinetics ; Female ; Fluconazole/pharmacokinetics ; Half-Life ; Healthy Volunteers ; Humans ; Janus Kinases/metabolism ; Male ; Metabolic Clearance Rate/drug effects ; Middle Aged ; Pyrazoles/pharmacokinetics ; Signal Transduction/drug effects |
| Chemical Substances | Enzyme Inhibitors ; Pyrazoles ; ruxolitinib (82S8X8XX8H) ; Fluconazole (8VZV102JFY) ; CYP2C9 protein, human (EC 1.14.13.-) ; Cytochrome P-450 CYP2C9 (EC 1.14.13.-) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; CYP3A4 protein, human (EC 1.14.14.55) ; Janus Kinases (EC 2.7.10.2) |
| Language | English |
| Publishing date | 2019-07-19 |
| Publishing country | Germany |
| Document type | Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 6820-2 |
| ISSN | 1432-0843 ; 0344-5704 ; 0943-9404 |
| ISSN (online) | 1432-0843 |
| ISSN | 0344-5704 ; 0943-9404 |
| DOI | 10.1007/s00280-019-03907-1 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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