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Clinical Pharmacokinetics of Vemurafenib

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Abstract

Vemurafenib is an orally administered small-molecule inhibitor of the oncogenic BRAF kinase that is indicated for the treatment of patients with unresectable or metastatic melanoma harbouring BRAF V600 mutations. Vemurafenib is absorbed rapidly after a single oral dose of 960 mg, reaching maximum drug concentration approximately 4 h after administration. Extensive accumulation occurs after multiple dosing at 960 mg twice daily. Steady state is achieved after approximately 15–21 days and exposure at steady state is relatively constant. Population pharmacokinetic analysis identified a vemurafenib half-life of ≈57 h and elimination appears to be predominantly via the hepatic route. Pharmacokinetic parameters are generally consistent regardless of age, sex or race. No dose adjustments are necessary for patients with mild or moderate hepatic or renal impairment, but the effects of severe hepatic or renal impairment on vemurafenib pharmacokinetics are uncertain. Vemurafenib appears to be a substrate and inducer of cytochrome P450 (CYP) 3A4, a moderate inhibitor of CYP1A2 and both a substrate and inhibitor of the drug efflux transporters P-glycoprotein and breast cancer resistance protein. The relationship between plasma vemurafenib concentrations and response remains to be clarified.

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References

  1. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75(1):50–83.

  2. Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. J Thorac Oncol. 2006;1(1):7–9.

    Article  PubMed  Google Scholar 

  3. Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov. 2014;13(12):928–42.

    Article  CAS  PubMed  Google Scholar 

  4. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26(22):3291–310.

    Article  CAS  PubMed  Google Scholar 

  5. Dhomen N, Marais R. New insight into BRAF mutations in cancer. Curr Opin Genet Dev. 2007;17(1):31–9.

    Article  CAS  PubMed  Google Scholar 

  6. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  CAS  PubMed  Google Scholar 

  7. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–47.

    Article  CAS  PubMed  Google Scholar 

  8. Amanuel B, Grieu F, Kular J, et al. Incidence of BRAF p.Val600Glu and p.Val600Lys mutations in a consecutive series of 183 metastatic melanoma patients from a high incidence region. Pathology. 2012;44(4):357–9.

    Article  CAS  PubMed  Google Scholar 

  9. Tiacci E, Schiavoni G, Forconi F, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood. 2012;119(1):192–5.

    Article  CAS  PubMed  Google Scholar 

  10. Xi L, Arons E, Navarro W, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood. 2012;119(14):3330–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Haroche J, Cohen-Aubart F, Emile JF, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013;121(9):1495–500.

    Article  CAS  PubMed  Google Scholar 

  12. Xing M, Alzahrani AS, Carson KA, et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013;309(14):1493–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Grisham RN, Iyer G, Garg K, et al. BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer. Cancer. 2013;119(3):548–54.

    Article  CAS  PubMed  Google Scholar 

  14. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29(26):3574–9.

    Article  CAS  PubMed  Google Scholar 

  15. Chesi M, Bergsagel PL. Molecular pathogenesis of multiple myeloma: basic and clinical updates. Int J Hematol. 2013;97(3):313–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28(3):466–74.

    Article  CAS  PubMed  Google Scholar 

  17. Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18(12):3242–9.

    Article  CAS  PubMed  Google Scholar 

  18. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855–67.

    Article  CAS  PubMed  Google Scholar 

  19. Tsai J, Lee JT, Wang W, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci. 2008;105(8):3041–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fisher R, Larkin J. Vemurafenib: a new treatment for BRAF-V600 mutated advanced melanoma. Cancer Manag Res. 2012;4:243–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF V600E and BRAF V600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zelboraf [package insert]. South San Francisco: Genentech USA, Inc.; 2016.

  27. Zelboraf [summary of product characteristics]. Welwyn Garden City: Roche Registration Limited; 2016.

  28. ZELBORAF® [product monograph]. Mississauga: Hoffmann-La Roche Limited; 2016.

  29. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(2):1867–76.

    Article  PubMed  Google Scholar 

  30. Shah N, Iyer RM, Mair HJ, et al. Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process. J Pharm Sci. 2013;102(3):967–81.

    Article  CAS  PubMed  Google Scholar 

  31. Janson B, Whittle J, Witney K, et al. Use of vemurafenib in a patient unable to swallow whole. J Oncol Pharm Pract. 2016;22(5):733–7.

    Article  CAS  PubMed  Google Scholar 

  32. Bautista F, Paci A, Minard-Colin V, et al. Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas. Pediatr Blood Cancer. 2014;61(6):1101–3.

    Article  CAS  PubMed  Google Scholar 

  33. Grippo JF, Zhang W, Heinzmann D, et al. A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma. Cancer Chemother Pharmacol. 2014;73(1):103–11.

    Article  CAS  PubMed  Google Scholar 

  34. Kim G, McKee AE, Ning YM, et al. FDA approval summary: vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation. Clin Cancer Res. 2014;20(19):4994–5000.

    Article  CAS  PubMed  Google Scholar 

  35. Ribas A, Zhang W, Chang I, et al. The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics. J Clin Pharmacol. 2014;54(4):368–74.

    Article  PubMed  Google Scholar 

  36. Mittapalli RK, Vaidhyanathan S, Sane R, et al. Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032). J Pharmacol Exp Ther. 2012;342:33–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Goldinger SM, Rinderknecht J, Dummer R, et al. A single-dose mass balance and metabolite-profiling study of vemurafenib in patients with metastatic melanoma. Pharmacol Res Perspect. 2015;3(2):e00113.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Mcintyre C, Colburn D, Kuhn M, et al. Effect of vemurafenib on the pharmacokinetics of a single dose of digoxin in patients with BRAFV600 mutation-positive metastatic malignancy [poster]. In: 2015 American Association of Pharmaceutical Scientists Annual Meeting and Exposition: Orlando; 25–29 Oct 2015.

  39. Zhang W, Xu C, Phipps AI. A physiologically based pharmacokinetic model to predict the effect of vemurafenib mediated P-glycoprotein inhibition on the pharmacokinetics of digoxin [poster]. In: 2015 American Association of Pharmaceutical Scientists Annual Meeting and Exposition: Orlando; 25–29 Oct 2015.

  40. Si L, Zhang X, Xu Z, et al. Phase 1 trial of vemurafenib (VEM) in chinese patients (pts) with BRAF mutation-positive unresectable or metastatic melanoma (MM). Pigment Cell Melanoma Res. 2015;28(6):813–4.

    Google Scholar 

  41. Yamazaki N, Kiyohara Y, Sugaya N, et al. Phase I/II study of vemurafenib in patients with unresectable or recurrent melanoma with BRAF V600 mutations. J Dermatol. 2015;42(7):661–6.

    Article  CAS  PubMed  Google Scholar 

  42. Héritier S, Jehanne M, Leverger G, et al. Vemurafenib use in an infant for high-risk Langerhans cell histiocytosis. JAMA Oncol. 2015;1(6):836–8.

    Article  PubMed  Google Scholar 

  43. Zhen Y, Thomas-Schoemann A, Sakji L, et al. An HPLC-UV method for the simultaneous quantification of vemurafenib and erlotinib in plasma from cancer patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2013;928:93–7.

    Article  CAS  PubMed  Google Scholar 

  44. Alvarez JC, Funck-Brentano E, Abe E, et al. A LC/MS/MS micro-method for human plasma quantification of vemurafenib. Application to treated melanoma patients. J Pharm Biomed Anal. 2014;97:29–32.

    Article  CAS  PubMed  Google Scholar 

  45. Nijenhuis CM, Rosing H, Schellens JH, et al. Development and validation of a high-performance liquid chromatography-tandem mass spectrometry assay quantifying vemurafenib in human plasma. J Pharm Biomed Anal. 2014;88:630–5.

    Article  CAS  PubMed  Google Scholar 

  46. Sparidans RW, Durmus S, Schinkel AH, et al. Liquid chromatography-tandem mass spectrometric assay for the mutated BRAF inhibitor vemurafenib in human and mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;889–890:144–7.

    Article  PubMed  Google Scholar 

  47. Bihan K, Sauzay C, Goldwirt L, et al. Development and validation of a rapid and simple LC-MS/MS method for quantification of vemurafenib in human plasma: application to a human pharmacokinetic study. Ther Drug Monit. 2015;37(1):132–6.

    Article  CAS  PubMed  Google Scholar 

  48. Vikingsson S, Stromqvist M, Svedberg A, et al. Novel rapid liquid chromatography tandem masspectrometry method for vemurafenib and metabolites in human plasma, including metabolite concentrations at steady-state. Biomed Chromatogr. 2016;30(8):1234–9.

    Article  CAS  PubMed  Google Scholar 

  49. Cleveland WS, Grosse E, Shyu WM. Local regression models. In: Statisical models in S. 2nd ed. Pacific Grove: Wadsworth & Brooks/Cole Advanced Books and Software; 1992. p. 309–376.

  50. Funck-Brentano E, Alvarez JC, Longvert C, et al. Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance. Ann Oncol. 2015;26(7):1470–5.

    CAS  PubMed  Google Scholar 

  51. Goldwirt L, Chami I, Feugeas JP, et al. Reply to ‘Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance’ by Funck-Brentano et al. [letter]. Ann Oncol. 2016;27(2):363–4.

    Article  CAS  PubMed  Google Scholar 

  52. Kramkimel N, Thomas-Schoemann A, Sakji L, et al. Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma. Target Oncol. 2016;11(1):59–69.

    Article  CAS  PubMed  Google Scholar 

  53. Hoffmann-La Roche. BRIM-P: a study of vemurafenib in pediatric patients with stage IIC or stage IV melanoma harboring BRAFV600 mutations [ClinicalTrials.gov identifier NCT01519323]. National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov. Accessed 20 Dec 2016.

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Acknowledgements

Medical writing assistance was provided by Melanie Sweetlove, MSc, ApotheCom, San Francisco, CA, USA and funded by F. Hoffmann-La Roche Ltd. The authors take full responsibility for the content of the paper.

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Authors and Affiliations

  1. Roche Innovation Center New York, 430 East 29th Street, New York, NY, 10016, USA

    Weijiang Zhang & Joseph F. Grippo

  2. F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Dominik Heinzmann

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Correspondence to Joseph F. Grippo.

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Preparation of this manuscript was funded by F. Hoffmann-La Roche Ltd.

Conflict of interest

Joseph F. Grippo, Dominik Heinzmann and Weijiang Zhang are employees of and hold stock/stock options in F. Hoffmann-La Roche Ltd.

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Zhang, W., Heinzmann, D. & Grippo, J.F. Clinical Pharmacokinetics of Vemurafenib. Clin Pharmacokinet 56, 1033–1043 (2017). https://doi.org/10.1007/s40262-017-0523-7

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