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14.06.2020 | Original Article

Assessment of effects of repeated oral doses of fedratinib on inhibition of cytochrome P450 activities in patients with solid tumors using a cocktail approach

verfasst von: Ken Ogasawara, Patricia M. LoRusso, Anthony J. Olszanski, Olivier Rixe, Christine Xu, Jian Yin, Maria Palmisano, Gopal Krishna

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2020

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Abstract

Purpose

Fedratinib, an oral selective kinase inhibitor with activity against both wild type and mutationally activated Janus kinase 2, has been approved for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis by the US Food and Drug Administration. In vitro studies indicated that fedratinib was an inhibitor of several cytochrome P450 (CYP) enzymes. The primary objective of this study was to evaluate the effects of repeated doses of fedratinib on the activity of CYP2D6, CYP2C19, and CYP3A4 in patients with solid tumors using a CYP probe cocktail.

Methods

An open-label, one-sequence, two-period, two-treatment crossover study was conducted. Patients were administered a single oral dose cocktail of metoprolol (100 mg), omeprazole (20 mg), and midazolam (2 mg) used as probe substrates for CYP2D6, CYP2C19, and CYP3A4 enzyme activities, respectively, without fedratinib on Day -1 or with fedratinib on Day 15.

Results

Coadministration of 500 mg once-daily doses of fedratinib for 15 days increased the mean area under the plasma concentration–time curve from time zero to infinity following a single-dose cocktail containing metoprolol (CYP2D6 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) by 1.77-fold (90% confidence interval [CI] 1.27–2.47) for metoprolol, 2.82-fold (90% CI 2.26–3.53) for omeprazole, and 3.84-fold (90% CI 2.62–5.63) for midazolam, respectively. The mean plasma Day 14/Day 1 ratio of 4β-hydroxycholesterol, an endogenous biomarker of CYP3A4 activity, was 0.59 (90% CI 0.54-0.66), suggesting a net inhibition of CYP3A4 by fedratinib.

Conclusion

Fedratinib is a weak inhibitor of CYP2D6, and a moderate inhibitor of CYP2C19 and CYP3A4. These results serve as the basis for dose modifications of these CYP substrate drugs when co-administered with fedratinib.

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Titel: Assessment of effects of repeated oral doses of fedratinib on inhibition of cytochrome P450 activities in patients with solid tumors using a cocktail approach
verfasst von: Ken Ogasawara
Patricia M. LoRusso
Anthony J. Olszanski
Olivier Rixe
Christine Xu
Jian Yin
Maria Palmisano
Gopal Krishna
Publikationsdatum: 14.06.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2020
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04102-3

Springer Medizin

Assessment of effects of repeated oral doses of fedratinib on inhibition of cytochrome P450 activities in patients with solid tumors using a cocktail approach