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Tyrosine kinase inhibitors and drug interactions: a review with practical recommendations

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  • New Trends in Clinical Oncology
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Abstract

The adverse effects associated to traditional chemotherapy are well known and broadly studied. In the recent years several tyrosine kinase inhibitors have been approved for cancer treatment and numerous are under investigation. These drugs target specific mutated/overexpressed tyrosin kinase receptors and frecuently their pharmacokinetic/pharmacodinamic behavior is not fully elucidated. These new drugs may interact with non-antineoplastic drugs leading to undesirable adverse effects. In this article, we will discuss different types of drug interactions and briefly review the pharmacokinetics and mechanisms of action of tyrosine kinase inhibitors in clinical use, with a particular emphasis on the risk of the occurrence of such interactions based on currently available scientific evidence.

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References

  1. Yancik R, Ganz PA, Varricchio CG, Conley B (2001) Perspectives on comorbidity and cancer in older patients: approaches to expand the knowledge base. J Clin Oncol 19:1147–1151

    PubMed  CAS  Google Scholar 

  2. Riechelmann RP, Tannock IF, Wang L et al (2007) Potential drug interactions and duplicate prescriptions among cancer patients. J Natl Cancer Inst 99:592–600

    Article  PubMed  Google Scholar 

  3. Goodman VL, Rock EP, Dagher R et al (2007) Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 13:1367–1373

    Article  PubMed  CAS  Google Scholar 

  4. Desar IM, Burger DM, Van Hoesel QG et al (2009) Pharmacokinetics of sunitinib in an obese patient with a GIST. Ann Oncol 20:599–600

    Article  PubMed  CAS  Google Scholar 

  5. Bello CL, Sherman L, Zhou J et al (2006) Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs 17:353–358

    Article  PubMed  CAS  Google Scholar 

  6. Moore M, Hirte HW, Siu L et al (2005) Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 16:1688–1694

    Article  PubMed  CAS  Google Scholar 

  7. Strumberg D, Clark JW, Awada A et al (2007) Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist 12:426–437

    Article  PubMed  CAS  Google Scholar 

  8. Rini BI (2006) Sorafenib. Expert Opin Pharmacother 7:453–461

    Article  PubMed  CAS  Google Scholar 

  9. FDA (2009) Drug label Nexavar approved 12/20/2005. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed on 02.03.2009

  10. Medina PJ, Goodin S (2008) Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther 30:1426–1447

    Article  PubMed  CAS  Google Scholar 

  11. Bence AK, Anderson EB, Halepota MA et al (2005) Phase I pharmacokinetic studies evaluating single and multiple doses of oral GW572016, a dual EGFR-ErbB2 inhibitor, in healthy subjects. Invest New Drugs 23:39–49

    Article  PubMed  CAS  Google Scholar 

  12. Burris HA 3rd (2004) Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 9[Suppl 3]:10–15

    Article  PubMed  CAS  Google Scholar 

  13. Reckmann AH, Fischer T, Peng B et al (2001) Effect of food on STI571 Glivec pharmacokinetics and bioavailability. Proc Am Soc Clin Oncol 20:abstract 1223

    Google Scholar 

  14. Sparano BA, Egorin MJ, Parise RA et al (2009) Effect of antacid on imatinib absorption. Cancer Chemother Pharmacol 63:525–528

    Article  PubMed  CAS  Google Scholar 

  15. Ling J, Fettner S, Lum BL et al (2008) Effect of food on the pharmacokinetics of erlotinib, an orally active epidermal growth factor receptor tyrosine-kinase inhibitor, in healthy individuals. Anticancer Drugs 19:209–216

    Article  PubMed  CAS  Google Scholar 

  16. FDA (2010) Drug label Erlotinib approved 15.09.2005. http://www.accessdata.fda.gov/drugsatfda/. Accessed on 16.09.2010

  17. Swaisland H, Laight A, Stafford L et al (2001) Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers. Clin Pharmacokinet 40:297–306

    Article  PubMed  CAS  Google Scholar 

  18. Swaisland HC, Smith RP, Laight A et al (2005) Single-dose clinical pharmacokinetic studies of gefitinib. Clin Pharmacokinet 44:1165–1177

    Article  PubMed  CAS  Google Scholar 

  19. Cohen MH, Williams GA, Sridhara R et al (2004) United States Food and Drug Administration Drug Approval summary: gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res 10:1212–1218

    Article  PubMed  CAS  Google Scholar 

  20. FDA (2010) Drug label Gefitinib approved 05.05.2003. http://www.accessdata.fda.gov/drugsatfda/. Accessed on 16.09.2010

  21. Wester MR, Johnson EF, Marques-Soares C et al (2003) Structure of mammalian cytochrome P450 2C5 complexed with diclofenac at 2.1 A resolution: evidence for an induced fit model of substrate binding. Biochemistry 42:9335–9345

    Article  PubMed  CAS  Google Scholar 

  22. Bertz RJ, Granneman GR (1997) Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 32:210–258

    Article  PubMed  CAS  Google Scholar 

  23. Blower P, de Wit R, Goodin S, Aapro M (2005) Drug-drug interactions in oncology: why are they important and can they be minimized? Crit Rev Oncol Hematol 55:117–142

    Article  PubMed  Google Scholar 

  24. Krishna DR, Klotz U (1994) Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet 26:144–160

    Article  PubMed  CAS  Google Scholar 

  25. Gibbs MA, Hosea NA (2003) Factors affecting the clinical development of cytochrome p450 3A substrates. Clin Pharmacokinet 42:969–984

    Article  PubMed  CAS  Google Scholar 

  26. Fuhr U (2000) Induction of drug metabolising enzymes: pharmacokinetic and toxicological consequences in humans. Clin Pharmacokinet 38:493–504

    Article  PubMed  CAS  Google Scholar 

  27. Rendic S (2002) Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev 34:83–448

    Article  PubMed  CAS  Google Scholar 

  28. Aubert RE, Stanek EJ, Yao J et al (2009) Risk of breast cancer recurrence in women initiating tamoxifen with CYP 2D6 inhibitors. J Clin Oncol 27[18 S]:abstr CRA508

    Google Scholar 

  29. Clarke SE (1998) In vitro assessment of human cytochrome P450. Xenobiotica 28:1167–1202

    Article  PubMed  CAS  Google Scholar 

  30. Evans WE, McLeod HL (2003) Pharmacogenomics: drug disposition, drug targets, and side effects. N Engl J Med 348:538–549

    Article  PubMed  CAS  Google Scholar 

  31. Phillips KA, Veenstra DL, Oren E et al (2001) Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 286:2270–2279

    Article  PubMed  CAS  Google Scholar 

  32. Schmucker DL (2001) Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging 18:837–851

    Article  PubMed  CAS  Google Scholar 

  33. FDA (2010) Drug label Sunitinib approved 2006. http://www.accessdata.fda.gov/drugsatfda/. Accessed on 16.09.2010

  34. Bello C, Houk B, Sherman L et al (2005) Effect of rifampicin on the pharmacokinetics of SU 11248 in healthy volunteers. J Clin Oncol 23[16 S]:3078

    Google Scholar 

  35. Washington C, Eli M, Bello C et al (2003) The effect of ketoconazole a potent CYP 3 A4 inhibitor on SU 011248 pharmacokinetics in Caucasian and Asian healthy subjects. Proc Am Soc Clin Oncol 22:abstr 553

    Google Scholar 

  36. Kane RC, Farrell AT, Saber H et al (2006) Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 12:7271–7278

    Article  PubMed  CAS  Google Scholar 

  37. Lathia C, Lettieri J, Cihon F et al (2006) Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol 57:685–692

    Article  PubMed  CAS  Google Scholar 

  38. FDA (2010) Drug label Lapatinib approved 2007. http://www.accessdata.fda.gov/drugsatfda/. Accessed on 16.09.2010

  39. Smith DA, Koch KM, Arya N et al (2009) Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects. Br J Clin Pharmacol 67:421–426

    Article  PubMed  CAS  Google Scholar 

  40. Pursche S, Schleyer E, von Bonin M et al (2008) Influence of enzyme-inducing antiepileptic drugs on trough level of imatinib in glioblastoma patients. Curr Clin Pharmacol 3:198–203

    Article  PubMed  CAS  Google Scholar 

  41. Bolton AE, Peng B, Hubert M et al (2004) Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol 53:102–106

    Article  PubMed  CAS  Google Scholar 

  42. Smith PF, Bullock JM, Booker BM et al (2004) Induction of imatinib metabolism by hypericum perforatum. Blood 104:1229–1230

    Article  PubMed  CAS  Google Scholar 

  43. Cutreix C, Peng B, Mehring G (2004) Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemother Pharmacol 54:290–294

    Google Scholar 

  44. van Erp NP, Gelderblom H, Karlsson MO et al (2007) Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin Cancer Res 13:7394–7400

    Article  PubMed  Google Scholar 

  45. Oostendorp RL, Buckle T, Beijnen JH et al (2009) The effect of P-gp (Mdr1a/1b), BCRP (Bcrp1) and P-gp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib. Invest New Drugs 27:31–40

    Article  PubMed  CAS  Google Scholar 

  46. O’Brien SG, Meinhardt P, Bond E et al (2003) Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer 89:1855–1859

    Article  PubMed  Google Scholar 

  47. Wang Y, Zhou L, Dutreix C et al (2008) Effects of imatinib (Glivec) on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in Chinese patients with chronic myelogenous leukaemia. Br J Clin Pharmacol 65:885–892

    Article  PubMed  CAS  Google Scholar 

  48. FDA (2010) Drug label Imatinib approved 2003. http://www.accessdata.fda.gov/drugsatfda/. Accessed on 16.09.2010

  49. Johnson JR, Cohen M, Sridhara R et al (2005) Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res 11:6414–6421

    Article  PubMed  CAS  Google Scholar 

  50. Lu JF, Eppler SM, Wolf J et al (2006) Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther 80:136–145

    Article  PubMed  CAS  Google Scholar 

  51. Li J, Zhao M, He P et al (2007) Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res 13:3731–3737

    Article  PubMed  CAS  Google Scholar 

  52. Hamilton M, Wolf JL, Rusk J et al (2006) Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 12:2166–2171

    Article  PubMed  CAS  Google Scholar 

  53. Rakhit A, Pantze MP, Fettner S et al (2008) The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (Sim-CYP) predicts in vivo metabolic inhibition. Eur J Clin Pharmacol 64:31–41

    Article  PubMed  CAS  Google Scholar 

  54. Yamamoto N, Horiike A, Fujisaka Y et al (2008) Phase I dose-finding and pharmacokinetic study of the oral epidermal growth factor receptor tyrosine kinase inhibitor Ro50-8231 (erlotinib) in Japanese patients with solid tumors. Cancer Chemother Pharmacol 61:489–496

    Article  PubMed  CAS  Google Scholar 

  55. Grenader T, Gipps M, Shavit L, Gabizon A (2007) Significant drug interaction: phenytoin toxicity due to erlotinib. Lung Cancer 57:404–406

    Article  PubMed  Google Scholar 

  56. Veeraputhiran M, Sundermeyer M (2008) Rhabdomyolysis resulting from pharmacologic interaction between erlotinib and simvastatin. Clin Lung Cancer 9:232–234

    Article  PubMed  CAS  Google Scholar 

  57. Swaisland HC, Ranson M, Smith RP et al (2005) Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin Pharmacokinet 44:1067–1081

    Article  PubMed  CAS  Google Scholar 

  58. McKillop D, Partridge EA, Kemp JV et al (2005) Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor. Mol Cancer Ther 4:641–649

    Article  PubMed  CAS  Google Scholar 

  59. Burris HA 3rd, Hurwitz HI, Dees EC et al (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23:5305–5313

    Article  PubMed  CAS  Google Scholar 

  60. Clark JW, Eder JP, Ryan D et al (2005) Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 11:5472–5480

    Article  PubMed  CAS  Google Scholar 

  61. Hidalgo M, Siu LL, Nemunaitis J et al (2001) Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267–3279

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Servicio de Oncología Médica, Hospital Clínico Virgen de la Victoria, Boulevard Luis Pasteur, s/n, ES-29010, Málaga, Spain

    Bella Pajares, Esperanza Torres, José Manuel Trigo, María Isabel Sáez, Nuria Ribelles, Begoña Jiménez & Emilio Alba

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  1. Bella Pajares
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  2. Esperanza Torres
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  3. José Manuel Trigo
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  4. María Isabel Sáez
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  6. Begoña Jiménez
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  7. Emilio Alba
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Corresponding author

Correspondence to Bella Pajares.

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Supported by an unrestricted educational grant from MSD Oncology

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Pajares, B., Torres, E., Trigo, J.M. et al. Tyrosine kinase inhibitors and drug interactions: a review with practical recommendations. Clin Transl Oncol 14, 94–101 (2012). https://doi.org/10.1007/s12094-012-0767-5

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  • DOI: https://doi.org/10.1007/s12094-012-0767-5

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