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Open Access 01-12-2021 | Graft-Versus-Host Disease | Original Article

Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice—a prospective single-center trial

Authors: Nora Isberner, Sabrina Kraus, Götz Ulrich Grigoleit, Fatemeh Aghai, Max Kurlbaum, Sebastian Zimmermann, Hartwig Klinker, Oliver Scherf-Clavel

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2021

Abstract

Purpose

Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects.

Methods

262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed.

Results

Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6–99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05).

Conclusion

Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.

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Title: Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice—a prospective single-center trial
Authors: Nora Isberner
Sabrina Kraus
Götz Ulrich Grigoleit
Fatemeh Aghai
Max Kurlbaum
Sebastian Zimmermann
Hartwig Klinker
Oliver Scherf-Clavel
Publication date: 01-12-2021
Publisher: Springer Berlin Heidelberg
Keywords: Graft-Versus-Host Disease
Graft-Versus-Host Disease
Ruxolitinib
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2021
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-021-04351-w

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