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Impact of fedratinib on the pharmacokinetics of transporter probe substrates using a cocktail approach

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Abstract

Introduction

Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate).

Methods

In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin.

Results

Plasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated.

Conclusions

These results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs.

Trial registration

Clinicaltrials.gov NCT04231435 on January 18, 2020.

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Data availability

Data requests may be submitted to Celgene, a Bristol Myers Squibb Company, at https://vivli.org/ourmember/celgene/ and must include a description of the research proposal.

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Furqan M, Mukhi N, Lee B, Liu D (2013) Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark Res 1(1):5. https://doi.org/10.1186/2050-7771-1-5

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, Silverman MH, Gilliland DG, Shorr J, Tefferi A (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pardanani A, Tefferi A, Jamieson C, Gabrail NY, Lebedinsky C, Gao G, Liu F, Xu C, Cao H, Talpaz M (2015) A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J 5(8):e335. https://doi.org/10.1038/bcj.2015.63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bristol Myers Squibb INREBIC (fedratinib) label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212327s000lbl.pdf. Accessed 10 Dec 2020

  6. Mehta J, Wang H, Iqbal SU, Mesa R (2014) Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma 55(3):595–600. https://doi.org/10.3109/10428194.2013.813500

    Article  PubMed  Google Scholar 

  7. Breccia M, Palandri F, Luciano L, Benevolo G, Bonifacio M, Caocci G, Castagnetti F, Palumbo GA, Iurlo A, Landi F (2018) Identification and assessment of frailty in older patients with chronic myeloid leukemia and myelofibrosis, and indications for tyrosine kinase inhibitor treatment. Ann Hematol 97(5):745–754. https://doi.org/10.1007/s00277-018-3258-0

    Article  CAS  PubMed  Google Scholar 

  8. Bartoszko J, Panzarella T, McNamara CJ, Lau A, Schimmer AD, Schuh AC, Sibai H, Maze D, Yee KWL, Devlin R, Gupta V (2017) Distribution and impact of comorbidities on survival and leukemic transformation in myeloproliferative neoplasm-associated myelofibrosis: a retrospective cohort study. Clin Lymphoma Myeloma Leuk 17(11):774–781. https://doi.org/10.1016/j.clml.2017.06.031

    Article  PubMed  Google Scholar 

  9. Newberry KJ, Naqvi K, Nguyen KT, Cardenas-Turanzas M, Florencia Tanaka M, Pierce S, Verstovsek S (2014) Comorbidities predict worse prognosis in patients with primary myelofibrosis. Cancer 120(19):2996–3002. https://doi.org/10.1002/cncr.28857

    Article  PubMed  Google Scholar 

  10. Ogasawara K, LoRusso PM, Olszanski AJ, Rixe O, Xu C, Yin J, Palmisano M, Krishna G (2020) Assessment of effects of repeated oral doses of fedratinib on inhibition of cytochrome P450 activities in patients with solid tumors using a cocktail approach. Cancer Chemother Pharmacol 86(1):87–95. https://doi.org/10.1007/s00280-020-04102-3

    Article  CAS  PubMed  Google Scholar 

  11. Ogasawara K, Xu C, Kanamaluru V, Siebers N, Surapaneni S, Ridoux L, Palmisano M, Krishna G (2020) Excretion balance and pharmacokinetics following a single oral dose of [(14)C]-fedratinib in healthy subjects. Cancer Chemother Pharmacol 86(2):307–314. https://doi.org/10.1007/s00280-020-04121-0

    Article  CAS  PubMed  Google Scholar 

  12. Ogasawara K, Xu C, Kanamaluru V, Palmisano M, Krishna G (2020) Effects of repeated oral doses of ketoconazole on a sequential ascending single oral dose of fedratinib in healthy subjects. Cancer Chemother Pharmacol 85(5):899–906. https://doi.org/10.1007/s00280-020-04067-3

    Article  CAS  PubMed  Google Scholar 

  13. Wu F, Krishna G, Surapaneni S (2020) Physiologically based pharmacokinetic modeling to assess metabolic drug-drug interaction risks and inform the drug label for fedratinib. Cancer Chemother Pharmacol 86(4):461–473. https://doi.org/10.1007/s00280-020-04131-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Giacomini KM, Huang SM (2013) Transporters in drug development and clinical pharmacology. Clin Pharmacol Ther 94(1):3–9. https://doi.org/10.1038/clpt.2013.86

    Article  CAS  PubMed  Google Scholar 

  15. International Transporter C, Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9(3):215–236. https://doi.org/10.1038/nrd3028

    Article  CAS  Google Scholar 

  16. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) (2020) In Vitro Drug Interaction Studies—Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. Accessed 11 Feb 2021

  17. Hibma JE, Zur AA, Castro RA, Wittwer MB, Keizer RJ, Yee SW, Goswami S, Stocker SL, Zhang X, Huang Y, Brett CM, Savic RM, Giacomini KM (2016) The effect of famotidine, a MATE1-selective inhibitor, on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacokinet 55(6):711–721. https://doi.org/10.1007/s40262-015-0346-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zamek-Gliszczynski MJ, Chu X, Cook JA, Custodio JM, Galetin A, Giacomini KM, Lee CA, Paine MF, Ray AS, Ware JA, Wittwer MB, Zhang L, International Transporter Consortium (2018) ITC commentary on metformin clinical drug-drug interaction study design that enables an efficacy- and safety-based dose adjustment decision. Clin Pharmacol Ther 104(5):781–784. https://doi.org/10.1002/cpt.1082

    Article  CAS  PubMed  Google Scholar 

  19. Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50(2):81–98. https://doi.org/10.2165/11534750-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  20. White CM (2002) A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin. J Clin Pharmacol 42(9):963–970

    Article  CAS  PubMed  Google Scholar 

  21. Iisalo E (1977) Clinical pharmacokinetics of digoxin. Clin Pharmacokinet 2(1):1–16. https://doi.org/10.2165/00003088-197702010-00001

    Article  CAS  PubMed  Google Scholar 

  22. Helsinn Therapeutics (2020) ALOXI® (palonosetron HCl injection) label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021372s021lbl.pdf. Accessed 21 Jan 2021

  23. University of Washington (2021) Drug Interaction Solutions. https://didb.druginteractionsolutions.org/drug/monograph/6225/ Accessed 9 Jan 2021

  24. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Center for Drug Evaluation and Research (2019) Application number: 212327Orig1s000 Multi-discipline review, Fedratinib. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212327Orig1s000MultidisciplineR.pdf. Accessed 10 Dec 2020

  26. U. S. Food and Drug Administration (2019) Drug development and drug interactions: table of substrates, inhibitors and inducers. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-3. Accessed 10 Dec 2020

  27. Stopfer P, Giessmann T, Hohl K, Sharma A, Ishiguro N, Taub ME, Zimdahl-Gelling H, Gansser D, Wein M, Ebner T, Muller F (2016) Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin. Clin Pharmacol Ther 100(3):259–267. https://doi.org/10.1002/cpt.406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Stopfer P, Giessmann T, Hohl K, Hutzel S, Schmidt S, Gansser D, Ishiguro N, Taub ME, Sharma A, Ebner T, Muller F (2018) Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions. Br J Clin Pharmacol 84(9):1941–1949. https://doi.org/10.1111/bcp.13609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lee D, Roh H, Son H, Jang SB, Lee S, Nam SY, Park K (2014) Pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers: a randomized, open-label, 3-period, crossover, multiple-dose study. Clin Ther 36(8):1171–1181. https://doi.org/10.1016/j.clinthera.2014.06.004

    Article  CAS  PubMed  Google Scholar 

  30. Stopfer P, Giessmann T, Hohl K, Sharma A, Ishiguro N, Taub ME, Jungnik A, Gansser D, Ebner T, Muller F (2018) Effects of metformin and furosemide on rosuvastatin pharmacokinetics in healthy volunteers: implications for their use as probe drugs in a transporter cocktail. Eur J Drug Metab Pharmacokinet 43(1):69–80. https://doi.org/10.1007/s13318-017-0427-9

    Article  CAS  PubMed  Google Scholar 

  31. Shin E, Shin N, Oh JH, Lee YJ (2017) High-dose metformin may increase the concentration of atorvastatin in the liver by inhibition of multidrug resistance-associated protein 2. J Pharm Sci 106(4):961–967. https://doi.org/10.1016/j.xphs.2016.11.020

    Article  CAS  PubMed  Google Scholar 

  32. Bachmakov I, Glaeser H, Fromm MF, Konig J (2008) Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on organic anion transporting polypeptides and organic cation transporter 1. Diabetes 57(6):1463–1469. https://doi.org/10.2337/db07-1515

    Article  CAS  PubMed  Google Scholar 

  33. Zhang M, Xu CR, Shamiyeh E, Liu F, Yin JY, von Moltke LL, Smith WB (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

    Article  CAS  PubMed  Google Scholar 

  34. Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, Masszi T, Mishchenko E, Jourdan E, Vannucchi AM, Drummond MW, Jurgutis M, Kuliczkowski K, Gheorghita E, Passamonti F, Neumann F, Patki A, Gao G, Tefferi A (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

    Article  PubMed  Google Scholar 

  35. Ogasawara K, Vince B, Xu C, Zhang M, Palmisano M, Krishna G (2020) A phase I study of the effect of repeated oral doses of pantoprazole on the pharmacokinetics of a single dose of fedratinib in healthy male subjects. Cancer Chemother Pharmacol 85(5):995–1001. https://doi.org/10.1007/s00280-020-04074-4

    Article  CAS  PubMed  Google Scholar 

  36. Li Q, Guo D, Dong Z, Zhang W, Zhang L, Huang SM, Polli JE, Shu Y (2013) Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs). Toxicol Appl Pharmacol 273(1):100–109. https://doi.org/10.1016/j.taap.2013.08.024

    Article  CAS  PubMed  Google Scholar 

  37. Li Q, Yang H, Guo D, Zhang T, Polli JE, Zhou H, Shu Y (2016) Effect of ondansetron on metformin pharmacokinetics and response in healthy subjects. Drug Metab Dispos 44(4):489–494. https://doi.org/10.1124/dmd.115.067223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) (2017) Application number: 210493Orig1s000 MULTI-DISCIPLINE REVIEW (Akynzeo). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210493Orig1s000MultidisciplineR.pdf. Accessed 18 Jan 2021

  39. Shah A, DeGroot T, Apseloff G (2006) Pharmacokinetic evaluation and safety profile of a 15-minute versus 30-second infusion of palonosetron in healthy subjects. J Clin Pharmacol 46(10):1139–1145. https://doi.org/10.1177/0091270006291625

    Article  CAS  PubMed  Google Scholar 

  40. Ogasawara K, Kam J, Thomas M, Liu L, Liu M, Xue Y, Surapaneni S, Carayannopoulos LN, Zhou S, Palmisano M, Krishna G (2021) Effects of strong and moderate CYP3A4 inducers on the pharmacokinetics of fedratinib in healthy adult participants. Cancer Chemother Pharmacol. https://doi.org/10.1007/s00280-021-04292-4

    Article  PubMed  Google Scholar 

  41. Wiebe ST, Giessmann T, Hohl K, Schmidt-Gerets S, Hauel E, Jambrecina A, Bader K, Ishiguro N, Taub ME, Sharma A, Ebner T, Mikus G, Fromm MF, Muller F, Stopfer P (2020) Validation of a drug transporter probe cocktail using the prototypical inhibitors rifampin, probenecid, verapamil, and cimetidine. Clin Pharmacokinet 59(12):1627–1639. https://doi.org/10.1007/s40262-020-00907-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kimura N, Okuda M, Inui K (2005) Metformin transport by renal basolateral organic cation transporter hOCT2. Pharm Res 22(2):255–259. https://doi.org/10.1007/s11095-004-1193-3

    Article  CAS  PubMed  Google Scholar 

  43. Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K (2007) Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol 74(2):359–371. https://doi.org/10.1016/j.bcp.2007.04.010

    Article  CAS  PubMed  Google Scholar 

  44. Morrissey KM, Stocker SL, Chen EC, Castro RA, Brett CM, Giacomini KM (2016) The effect of Nizatidine, a MATE2K selective inhibitor, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers. Clin Pharmacokinet 55(4):495–506. https://doi.org/10.1007/s40262-015-0332-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nakada T, Kudo T, Kume T, Kusuhara H, Ito K (2018) Quantitative analysis of elevation of serum creatinine via renal transporter inhibition by trimethoprim in healthy subjects using physiologically-based pharmacokinetic model. Drug Metab Pharmacokinet 33(1):103–110. https://doi.org/10.1016/j.dmpk.2017.11.314

    Article  CAS  PubMed  Google Scholar 

  46. Mathialagan S, Rodrigues AD, Feng B (2017) Evaluation of renal transporter inhibition using creatinine as a substrate in vitro to assess the clinical risk of elevated serum creatinine. J Pharm Sci 106(9):2535–2541. https://doi.org/10.1016/j.xphs.2017.04.009

    Article  CAS  PubMed  Google Scholar 

  47. Tsuda M, Terada T, Ueba M, Sato T, Masuda S, Katsura T, Inui K (2009) Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J Pharmacol Exp Ther 329(1):185–191. https://doi.org/10.1124/jpet.108.147918

    Article  CAS  PubMed  Google Scholar 

  48. Yin J, Wang J (2016) Renal drug transporters and their significance in drug-drug interactions. Acta Pharm Sin B 6(5):363–373. https://doi.org/10.1016/j.apsb.2016.07.013

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank all study participants and clinical study team members from both Bristol Myers Squibb and PPD. The clinical trial reported in this manuscript was designed and sponsored by Bristol Myers Squibb. Medical writing support was provided by Alex Loeb, PhD, of Chrysalis Medical Communications, Hamilton, NJ, and funded by Bristol Myers Squibb.

Funding

This trial was sponsored by Bristol Myers Squibb.

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Authors and Affiliations

  1. Bristol Myers Squibb, Summit, NJ, USA

    Ken Ogasawara, Mark Thomas, Michael Thomas, Liangang Liu, Mary Liu, Yongjun Xue, Sekhar Surapaneni, Leonidas N. Carayannopoulos, Simon Zhou, Maria Palmisano & Gopal Krishna

  2. PPD Development LP, Austin, TX, USA

    Rebecca N. Wood-Horrall

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  1. Ken Ogasawara
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Contributions

KO and GK contributed to study design, data analysis, interpretation, and drafted manuscript. LNC, LL, and ML contributed to study design, data analysis, and interpretation. RNW-H and YX contributed to data acquisition and interpretation. MaT contributed to study design, data acquisition, and interpretation. MiT, SS, SZ, and MP contributed to study design and interpretation. All authors critically reviewed the draft manuscript and approved the final version to be published and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Ken Ogasawara.

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Conflict of interest

K.O., Ma.T., Mi.T., L.L, M.L, Y.X, S.S, L.N.C., S.Z., M.P., and G.K. are employees of, and hold equity ownership in, Bristol Myers Squibb. R.N.W–H. is an employee of PPD Development LP.

Ethics approval

The protocol complied with recommendations of the 18th World Health Congress (Helsinki, 1964) and all applicable amendments. The protocol and its amendment were submitted to an institutional review board (Salus Independent Review Board, Austin, TX) for review and written approval.

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Written informed consent was obtained prior to the conduct of any study-related procedures.

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All authors critically reviewed the draft manuscript and approved the final version to be published and agree to be accountable for all aspects of the work.

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Ogasawara, K., Wood-Horrall, R.N., Thomas, M. et al. Impact of fedratinib on the pharmacokinetics of transporter probe substrates using a cocktail approach. Cancer Chemother Pharmacol 88, 941–952 (2021). https://doi.org/10.1007/s00280-021-04346-7

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