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01-07-2020 | Metoprolol | 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

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

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2020

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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Vainchenker W, Constantinescu SN (2013) JAK/STAT signaling in hematological malignancies. Oncogene 32(21):2601–2613. https://doi.org/10.1038/onc.2012.347 CrossRef

Romano M, Sollazzo D, Trabanelli S, Barone M, Polverelli N, Perricone M et al (2017) Mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in myelofibrosis. Oncoimmunology 6(10):e1345402. https://doi.org/10.1080/2162402X.2017.1345402 CrossRefPubMedPubMedCentral

U.S. Food and Drug Administration. INREBIC (fedratinib) label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212327s000lbl.pdf. Accessed Nov 12 2019

Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D et al (2015) Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol 1(5):643–651. https://doi.org/10.1001/jamaoncol.2015.1590 CrossRefPubMed

Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Tiu RV, Zachee P et al (2017) Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol 4(7):e317–e324. https://doi.org/10.1016/S2352-3026(17)30088-1 CrossRefPubMed

Tefferi A (2016) Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 91(12):1262–1271. https://doi.org/10.1002/ajh.24592 CrossRefPubMed

Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM et al (2011) Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol 29(7):789–796. https://doi.org/10.1200/JCO.2010.32.8021 CrossRefPubMedPubMedCentral

Zhang M, Xu CR, Shamiyeh E, Liu F, Yin JY, von Moltke LL et al (2014) A randomized, placebo-controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK2 inhibitor fedratinib (SAR302503) in healthy volunteers. J Clin Pharmacol 54(4):415–421. https://doi.org/10.1002/jcph.218 CrossRefPubMed

Ogasawara K, Zhou S, Krishna G, Palmisano M, Li Y (2019) Population pharmacokinetics of fedratinib in patients with myelofibrosis, polycythemia vera, and essential thrombocythemia. Cancer Chemother Pharmacol 84(4):891–898. https://doi.org/10.1007/s00280-019-03929-9 CrossRefPubMedPubMedCentral

10.

Pardanani A, Tefferi A, Jamieson C, Gabrail NY, Lebedinsky C, Gao G et al (2015) A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J. 5:e335. https://doi.org/10.1038/bcj.2015.63 CrossRefPubMedPubMedCentral

11.

Zhang M, Xu C, Ma L, Shamiyeh E, Yin J, von Moltke LL et al (2015) Effect of food on the bioavailability and tolerability of the JAK2-selective inhibitor fedratinib (SAR302503): results from two phase I studies in healthy volunteers. Clin Pharmacol Drug Dev 4(4):315–321. https://doi.org/10.1002/cpdd.161 CrossRefPubMed

12.

U.S. Food and Drug Administration. Clinical Drug Interaction Studies - Study Design, Data Analysis, and Clinical Implications, Guidance for Industry. 2017. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-study-design-data-analysis-and-clinical-implications-guidance. Accessed Nov 12 2019

13.

U.S. Food and Drug Administration. In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies, Guidance for Industry. 2017. https://www.fda.gov/files/drugs/published/In-Vitro-Metabolism–and-Transporter–Mediated-Drug-Drug-Interaction-Studies-Guidance-for-Industry.pdf. Accessed Apr 2 2020

14.

Turpault S, Brian W, Van Horn R, Santoni A, Poitiers F, Donazzolo Y et al (2009) Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol 68(6):928–935. https://doi.org/10.1111/j.1365-2125.2009.03548.x CrossRefPubMedPubMedCentral

15.

U.S. Food and Drug Administration. PRILOSEC (omeprazole) label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019810s102,022056s019lbl.pdf. Accessed Nov 12 2019

16.

Bodin K, Bretillon L, Aden Y, Bertilsson L, Broome U, Einarsson C et al (2001) Antiepileptic drugs increase plasma levels of 4beta-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4. J Biol Chem 276(42):38685–38689. https://doi.org/10.1074/jbc.M105127200 CrossRefPubMed

17.

Diczfalusy U, Nylen H, Elander P, Bertilsson L (2011) 4beta-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. Br J Clin Pharmacol 71(2):183–189. https://doi.org/10.1111/j.1365-2125.2010.03773.x CrossRefPubMedPubMedCentral

18.

Zhou H, Tong Z, McLeod JF (2004) “Cocktail” approaches and strategies in drug development: valuable tool or flawed science? J Clin Pharmacol 44(2):120–134. https://doi.org/10.1177/0091270003261333 CrossRefPubMed

19.

U.S. Food and Drug Administration. LOPRESSOR (metoprolol tartrate) label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017963s068lbl.pdf. Accessed Nov 12 2019

20.

Juif PE, Boehler M, Donazzolo Y, Bruderer S, Dingemanse J (2017) A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects. Eur J Clin Pharmacol 73(9):1121–1128. https://doi.org/10.1007/s00228-017-2282-7 CrossRefPubMed

Title: Assessment of effects of repeated oral doses of fedratinib on inhibition of cytochrome P450 activities in patients with solid tumors using a cocktail approach
Authors: Ken Ogasawara
Patricia M. LoRusso
Anthony J. Olszanski
Olivier Rixe
Christine Xu
Jian Yin
Maria Palmisano
Gopal Krishna
Publication date: 01-07-2020
Publisher: Springer Berlin Heidelberg
Keywords: Metoprolol
Solid Tumor
Pharmacokinetics
Omeprazole
Midazolam
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04102-3

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