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Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 1, pp 107–113 | Cite as

Associations among regorafenib concentrations, severe adverse reactions, and ABCG2 and OATP1B1 polymorphisms

  • Akimitsu MaedaEmail author
  • Kei Irie
  • Hitoshi Ando
  • Ayako Hasegawa
  • Hiroya Taniguchi
  • Shigenori Kadowaki
  • Kei Muro
  • Masahiro Tajika
  • Masahiro Aoki
  • Kazuhide Inaguma
  • Masaki Kajita
  • Akio Fujimura
  • Shoji Fukushima
Original Article

Abstract

Purpose

The ability of predicting severe adverse reactions caused by regorafenib is important. We evaluated regorafenib concentrations for adverse reaction risks and assessed the relevance of laboratory values and gene polymorphisms.

Methods

A total of 28 Japanese cancer patients who were treated with regorafenib were evaluated for the steady state of serum regorafenib concentrations and adverse reactions for 28 days. In addition, we determined the association of regorafenib concentrations with ABCG2 and OATP1B1 polymorphisms, which are regorafenib transporters.

Results

Regorafenib concentrations were significantly higher in the group with Grade 2 or higher total bilirubin elevation and thrombocytopenia compared with the group with grades 0 or 1 [3.45 (2.18–7.31) vs. 1.76 (0.26–2.77) µg/mL, P = 0.01 and 3.45 (2.12–7.31) vs. 1.76 (0.26–2.77) µg/mL, P = 0.02, respectively]. A strong association was noted between serum regorafenib concentrations and total bilirubin levels, but the physical and genetic factors predicting regorafenib pharmacokinetics could not be clarified.

Conclusions

Regorafenib concentrations were associated with total bilirubin elevation and thrombocytopenia. Total serum bilirubin could be a useful marker when estimating regorafenib pharmacokinetics.

Keywords

Adverse reactions Bilirubin Pharmacokinetics Regorafenib OATP1B1 SLCO1B1 

Notes

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

References

  1. 1.
    Grothey A, Van Cutsem E, Sobrero A et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303–312CrossRefGoogle Scholar
  2. 2.
    Mross K, Frost A, Steinbild S et al (2012) A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res 18:2658–2667CrossRefGoogle Scholar
  3. 3.
    Osawa H (2017) Response to regorafenib at an initial dose of 120 mg as salvage therapy for metastatic colorectal cancer. Mol Clin Oncol 6:365–372CrossRefGoogle Scholar
  4. 4.
    Kort A, Durmus S, Sparidans RW et al (2015) Brain and testis accumulation of regorafenib is restricted by breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1). Pharm Res 32:2205–2216CrossRefGoogle Scholar
  5. 5.
    Ohya H, Shibayama Y, Ogura J et al (2015) Regorafenib is transported by the organic anion transporter 1B1 and the multidrug resistance protein 2. Biol Pharm Bull 38:582–586CrossRefGoogle Scholar
  6. 6.
    Maeda A, Ando H, Ura T et al (2017) Association between ABCG2 and SLCO1B1 polymorphisms and adverse drug reactions to regorafenib: a preliminary study. Int J Clin Pharmacol Ther 55:409–415CrossRefGoogle Scholar
  7. 7.
    Allard M, Khoudour N, Rousseau B et al (2017) Simultaneous analysis of regorafenib and sorafenib and three of their metabolites in human plasma using LC-MS/MS. J Pharm Biomed Anal 142:42–48CrossRefGoogle Scholar
  8. 8.
    Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl 48:452–458CrossRefGoogle Scholar
  9. 9.
    Sunakawa Y, Furuse J, Okusaka T et al (2014) Regorafenib in Japanese patients with solid tumors: phase I study of safety, efficacy, and pharmacokinetics. Investig New Drugs 32:104–112CrossRefGoogle Scholar
  10. 10.
    Strumberg D, Scheulen ME, Schultheis B et al (2012) Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer 106:1722–1727CrossRefGoogle Scholar
  11. 11.
    Cui Y, Konig J, Leier I et al (2001) Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem 276:9626–9630CrossRefGoogle Scholar
  12. 12.
    Briz O, Serrano MA, MacIas RI et al (2003) Role of organic anion-transporting polypeptides, OATP-A, OATP-C and OATP-8, in the human placenta-maternal liver tandem excretory pathway for foetal bilirubin. Biochem J 371:897–905CrossRefGoogle Scholar
  13. 13.
    Campbell SD, de Morais SM, Xu JJ (2004) Inhibition of human organic anion transporting polypeptide OATP 1B1 as a mechanism of drug-induced hyperbilirubinemia. Chem Biol Interact 150:179–187CrossRefGoogle Scholar
  14. 14.
    Zhao B, Zhao H (2017) Incidence and risk of regorafenib-induced hepatotoxicity. Oncotarget 8:84102–84111Google Scholar
  15. 15.
    Keppler D (2014) The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia. Drug Metab Dispos 42:561–565CrossRefGoogle Scholar
  16. 16.
    Schultheis B, Folprecht G, Kuhlmann J et al (2013) Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol 24:1560–1567CrossRefGoogle Scholar
  17. 17.
    Teft WA, Welch S, Lenehan J et al (2015) OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan-based chemotherapy. Br J Cancer 112:857–865CrossRefGoogle Scholar
  18. 18.
    Nozawa T, Minami H, Sugiura S et al (2005) Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 33:434–439CrossRefGoogle Scholar
  19. 19.
    Pasanen MK, Fredrikson H, Neuvonen PJ et al (2007) Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 82:726–733CrossRefGoogle Scholar
  20. 20.
    Nishizato Y, Ieiri I, Suzuki H et al (2003) Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 73:554–565CrossRefGoogle Scholar
  21. 21.
    Ieiri I, Higuchi S, Sugiyama Y (2009) Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Expert Opin Drug Metab Toxicol 5:703–729CrossRefGoogle Scholar
  22. 22.
    Deng JW, Song IS, Shin HJ et al (2008) The effect of SLCO1B1*15 on the disposition of pravastatin and pitavastatin is substrate dependent: the contribution of transporting activity changes by SLCO1B1*15. Pharmacogenet Genom 18:424–433CrossRefGoogle Scholar
  23. 23.
    Choi JH, Lee MG, Cho JY et al (2008) Influence of OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans. Clin Pharmacol Ther 83:251–257CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Akimitsu Maeda
    • 1
    Email author
  • Kei Irie
    • 2
    • 3
  • Hitoshi Ando
    • 4
  • Ayako Hasegawa
    • 1
  • Hiroya Taniguchi
    • 5
  • Shigenori Kadowaki
    • 5
  • Kei Muro
    • 5
  • Masahiro Tajika
    • 6
  • Masahiro Aoki
    • 7
  • Kazuhide Inaguma
    • 1
  • Masaki Kajita
    • 1
  • Akio Fujimura
    • 8
  • Shoji Fukushima
    • 3
  1. 1.Department of PharmacyAichi Cancer Center HospitalNagoyaJapan
  2. 2.Department of PharmacyKobe City Hospital Organization, Kobe City Medical Center General HospitalKobeJapan
  3. 3.Department of Pharmaceutics, Faculty of Pharmaceutical ScienceKobe Gakuin UniversityKobeJapan
  4. 4.Department of Cellular and Molecular Function AnalysisKanazawa University Graduate School of Medical SciencesKanazawaJapan
  5. 5.Department of Clinical OncologyAichi Cancer Center HospitalNagoyaJapan
  6. 6.Department of EndoscopyAichi Cancer Center HospitalNagoyaJapan
  7. 7.Division of Molecular PathologyAichi Cancer Center Research InstituteNagoyaJapan
  8. 8.Division of Clinical Pharmacology, Department of PharmacologyJichi Medical UniversityShimotsukeJapan

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