Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-266476
- 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 wasPurpose 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.…
Autor(en): | Nora Isberner, Sabrina Kraus, Götz Ulrich Grigoleit, Fatemeh Aghai, Max Kurlbaum, Sebastian Zimmermann, Hartwig Klinker, Oliver Scherf-Clavel |
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URN: | urn:nbn:de:bvb:20-opus-266476 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) |
Medizinische Fakultät / Medizinische Klinik und Poliklinik II | |
Fakultät für Chemie und Pharmazie / Institut für Pharmazie und Lebensmittelchemie | |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Cancer Chemotherapy and Pharmacology |
ISSN: | 1432-0843 |
Erscheinungsjahr: | 2021 |
Band / Jahrgang: | 88 |
Heft / Ausgabe: | 6 |
Seitenangabe: | 973-983 |
Originalveröffentlichung / Quelle: | Cancer Chemotherapy and Pharmacology 2021, 88(6):973-983. DOI: 10.1007/s00280-021-04351-w |
DOI: | https://doi.org/10.1007/s00280-021-04351-w |
PubMed-ID: | https://pubmed.ncbi.nlm.nih.gov/34505930 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | CYP2C9; CYP3A4; Ruxolitinib; graft versus host disease; therapeutic drug monitoring; toxicity |
Datum der Freischaltung: | 26.07.2022 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |