Skip to main content
SpringerLink
Log in

Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors

Focus on 4-Anilinoquinazolines

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

The 4-anilinoquinazolines (gefitinib, erlotinib and lapatinib) are members of a class of potent and selective inhibitors of the human epidermal growth factor receptor (HER) family of tyrosine kinases that have been developed to treat patients with tumours with defined genetic alterations of the HER tyrosine kinase domain. They are characterized by a moderate rate of absorption after oral administration with peak plasma concentrations at several hours post-dose. Absolute bioavailability of gefitinib and erlotinib is about 60%. Low bioavailability is assumed for lapatinib. The drugs are extensively distributed in human tissues, including tumour tissues, have a large volume of distribution at least 3-fold exceeding the volume of body water and are extensively (about 95%) protein bound to α1-acid glycoprotein and albumin.

Existing human data for gefitinib and erlotinib indicate that these substances penetrate into the central nervous system and accumulate in brain tumours, possibly due to leaks in the blood-brain barrier. Gefitinib, erlotinib and the absorbed fraction of lapatinib undergo extensive metabolism — mainly via hepatic and intestinal cytochrome P450 (CYP) 3A4 and also via CYP2D6 (gefitinib) and CYP1A2 (erlotinib) — and are primarily eliminated by biotransformation. The excretion of unchanged gefitinib, erlotinib, lapatinib and their metabolites occurs predominantly in the faeces and only a minor fraction is excreted in the urine. No relevant effects of age, sex, bodyweight or race on their pharmacokinetics have been reported to date.

Limited available data indicate that genetic polymorphisms in enzymes and transporters involved in the pharmacokinetics of gefitinib (CYP2D6) and erlotinib (CYP3A4, CYP3A5 and ABCG2 [breast cancer resistance protein]) alter the exposure to these drugs. Modification of drug dose should be considered in patients with severe hepatic impairment receiving these tyrosine kinase inhibitors and in current smokers receiving erlotinib. Existing recommendations for dose adjustment (i.e. a dose decrement or increment for gefitinib, erlotinib and lapatinib in the presence of CYP3A4 inhibitors or inducers, respectively; a dose increase for erlotinib in smoking patients) need to be validated in clinical studies. Further investigations are required to explain the large interindividual variability in the pharmacokinetics of these drugs and to assess the clinical relevance of interaction potential and inhibitory effects on the metabolizing enzymes and transporters.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Fig. 1
Table II
Table III
Table IV

Similar content being viewed by others

References

  1. Van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev 2009; 35(8): 692–706

    Article  PubMed  CAS  Google Scholar 

  2. Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs 2000; 59(4): 753–67

    Article  PubMed  CAS  Google Scholar 

  3. Ciardiello F, Caputo R, Bianco R, et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 2001; 7(5): 1459–65

    PubMed  CAS  Google Scholar 

  4. Cohen MH, Williams GA, Sridhara R, et al. United States Food and Drug Administration drug approval summary: gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res 2004; 10(4): 1212–8

    Article  PubMed  CAS  Google Scholar 

  5. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (the IDEAL 1 trial) [published erratum appears in J Clin Oncol 2004; 22(23): 4811]. J Clin Oncol 2003; 21(12): 2237–46

    Article  PubMed  CAS  Google Scholar 

  6. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003; 290(16): 2149–58

    Article  PubMed  CAS  Google Scholar 

  7. Moyer JD, Barbacci EG, Iwata KK, et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 1997; 57(21): 4838–48

    PubMed  CAS  Google Scholar 

  8. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353(2): 123–32

    Article  PubMed  CAS  Google Scholar 

  9. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25(15): 1960–6

    Article  PubMed  CAS  Google Scholar 

  10. Miksad RA, Schnipper L, Goldstein M. Does a statistically significant survival benefit of erlotinib plus gemcitabine for advanced pancreatic cancer translate into clinical significance and value?. J Clin Oncol 2007; 25(28): 4506–7

    Article  PubMed  Google Scholar 

  11. Nelson MH, Dolder CR. Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann Pharmacother 2006; 40: 261–9

    Article  PubMed  CAS  Google Scholar 

  12. Burris III HA, Taylor CW, Jones SF, et al. A phase I and pharmacokinetic study of oral lapatinib administration once or twice daily in patients with solid malignancies. Clin Cancer Res 2009; 15(21): 6702–8

    Article  PubMed  CAS  Google Scholar 

  13. Bilancia D, Rosati G, Dinota A, et al. Lapatinib in breast cancer. Ann Oncol 2007; 18(6): 26–30

    Article  Google Scholar 

  14. Denny WA. The 4-anilinoquinazoline class of inhibitors of the erbB family of receptor tyrosine kinases. Farmaco 2001; 56(1-2): 51–6

    Article  PubMed  CAS  Google Scholar 

  15. Carpenter G, Cohen S. Epidermal growth factor. J Biol Chem 1990; 265: 7709–12

    PubMed  CAS  Google Scholar 

  16. Pao W, Miller VA. Epidermal growth factor receptor mutations, small molecule kinase inhibitors and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005; 23: 2556–68

    Article  PubMed  CAS  Google Scholar 

  17. Pollack VA, Savage DM, Baker DA, et al. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 1999; 291(2): 739–48

    PubMed  CAS  Google Scholar 

  18. Rusnak DW, Lackey K, Affleck K, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 2001; 1(2): 85–94

    PubMed  CAS  Google Scholar 

  19. Xia W, Mulin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 2002; 21: 6255–63

    Article  PubMed  CAS  Google Scholar 

  20. Tevaarwerk AJ, Kolesar JM. Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther 2009; 31(2): 2332–48

    Article  PubMed  CAS  Google Scholar 

  21. Govindan R. A review of epidermal growth factor receptor/HER2 inhibitors in the treatment of patients with non-small-cell lung cancer. Clin Lung Cancer 2010; 11(1): 8–12

    Article  PubMed  CAS  Google Scholar 

  22. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004; 101(36): 13306–11

    Article  PubMed  CAS  Google Scholar 

  23. Hirsch FR, Witta S. Biomarkers for prediction of sensitivity to EGFR inhibitors in non-small cell lung cancer. Curr Opin Oncol 2005; 17: 118–22

    Article  PubMed  CAS  Google Scholar 

  24. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361(10): 947–57

    Article  PubMed  CAS  Google Scholar 

  25. Hirata A, Ogawa S, Kometani T, et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 2002; 62(9): 2554–60

    PubMed  CAS  Google Scholar 

  26. Wakeling AE, Guy SP, Woodburn JR, et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 2002; 62(20): 5749–54

    PubMed  CAS  Google Scholar 

  27. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009; 28 Suppl. 1: 24–31

    Article  CAS  Google Scholar 

  28. Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer 2009; 10(4): 281–9

    Article  PubMed  CAS  Google Scholar 

  29. Burris III HA, Hurwitz HI, Dees EC, et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal groth factor receptor tyrosine kinases, in heavily pre-treated patients with metastatic carcinomas. J Clin Oncol 2005; 23: 5305–13

    Article  PubMed  CAS  Google Scholar 

  30. Choi YJ, Rho JK, Jeon BS, et al. Combined inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors. Cancer Chemother Pharmacol 2010; 66(2): 381–8

    Article  PubMed  CAS  Google Scholar 

  31. Lawrence DS, Niu J. Protein kinase inhibitors: the tyrosine-specific protein kinases. Pharmacol Ther 1998; 77(2): 81–114

    Article  PubMed  CAS  Google Scholar 

  32. European Medicines Agency. Iressa® 250 mg film-coated tablets: summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001016/WC500036358.pdf [Accessed 2011 Mar 16]

  33. Tarceva® (erlotinib) tablets: US prescribing information [online]. Available from URL: http://www.gene.com/gene/products/information/pdf/tarceva-prescribing.pdf [Accessed 2011 Mar 16]

  34. Polli JW, Humphreyes JE, Harmon KA, et al. The role of efflux and uptake transporters in N-3-chloro-4-[(3-fluorbenzyl)oxy]phenyl-6-[5 ([2-(methylsul-fonyl)ethyl]aminomethyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab Dispos 2008; 36(4): 695–701

    Article  PubMed  CAS  Google Scholar 

  35. Tyverb® (lapatinib) tablets: US prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022059s007lbl.pdf [Accessed 2011 Mar 16]

  36. Herbst RS, Maddox AM, Rothenberg ML, et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol 2002; 20(18): 3815–25

    Article  PubMed  CAS  Google Scholar 

  37. Swaisland H, Laight A, Stafford L, et al. Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers. Clin Pharmacokinet 2001; 40(4): 297–306

    Article  PubMed  CAS  Google Scholar 

  38. Jones HK, Stafford LE, Swaisland HC, et al. A sensitive assay for ZD1839 (Iressa) in human plasma by liquid-liquid extraction and high performance liquid chromatography with mass spectrometric detection: validation and use in phase I clinical trials. J Pharm Biomed Anal 2002; 29(1-2): 221–8

    Article  PubMed  CAS  Google Scholar 

  39. Hidalgo M, Siu LL, Nemunaitis J, et al. 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 2001; 19(13): 3267–79

    PubMed  CAS  Google Scholar 

  40. Zhao M, He P, Rudek MA, et al. Specific method for determination of OSI-774 and its metabolite OSI-420 in human plasma by using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 793(2): 413–20

    Article  PubMed  CAS  Google Scholar 

  41. Lepper ER, Swain SM, Tan AR, et al. Liquid-chromatographic determination of erlotinib (OSI-774), an epidermal growth factor receptor tyrosine kinase inhibitor. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 796(1): 181–8

    Article  PubMed  CAS  Google Scholar 

  42. Masters AR, Sweeney CJ, Jones DR. The quantification of erlotinib (OSI-774) and OSI-420 in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 848(2): 379–83

    Article  PubMed  CAS  Google Scholar 

  43. Zhang W, Siu LL, Moore MJ, et al. Simultaneous determination of OSI-774 and its major metabolite OSI-420 in human plasma by using HPLC with UV detection. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 814(1): 143–7

    Article  PubMed  CAS  Google Scholar 

  44. Bai F, Freeman III BB, Fraga CH, et al. Determination of lapatinib (GW572016) in human plasma by liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS). J Chromatogr 2006; 831: 169–75

    Article  CAS  Google Scholar 

  45. Haouala A, Zanolari B, Rochat B, et al. Therapeutic drug monitoring of the new targeted anticancer agents imatinib, nilotinib, dasatinib, sunitinib, sorafenib and lapatinib by LC tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877(22): 1982–96

    Article  PubMed  CAS  Google Scholar 

  46. Roche S, McMahon G, Clynes M, et al. Development of a high-performance liquid chromatographic-mass spectrometric method for the determination of cellular levels of the tyrosine kinase inhibitors lapatinib and dasatinib. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877(31): 3982–90

    Article  PubMed  CAS  Google Scholar 

  47. Swaisland HC, Smith RP, Laight A, et al. Single-dose clinical pharmacokinetic studies of gefitinib. Clin Pharmacokinet 2005; 44(11): 1165–77

    Article  PubMed  CAS  Google Scholar 

  48. Li J, Brahmer J, Messersmith W, et al. Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: in vitro and in cancer patients. Invest New Drugs 2006; 24(4): 291–7

    Article  PubMed  CAS  Google Scholar 

  49. Daw NC, Furman WL, Stewart CF, et al. Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children’s Oncology Group study. J Clin Oncol 2005; 23(25): 6172–80

    Article  PubMed  CAS  Google Scholar 

  50. Ranson M, Hammond LA, Ferry D, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002; 20(9): 2240–50

    Article  PubMed  CAS  Google Scholar 

  51. Nakagawa K, Tamura T, Negoro S, et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (’Iressa’, ZD1839) in Japanese patients with solid malignant tumors. Ann Oncol 2003; 14(6): 922–30

    Article  PubMed  CAS  Google Scholar 

  52. Bergman E, Forsell P, Persson EM, et al. Pharmacokinetics of gefitinib in humans: the influence of gastrointestinal factors. Int J Pharm 2007; 341(1-2): 134–42

    Article  PubMed  CAS  Google Scholar 

  53. Cantarini MV, McFarquhar T, Smith RP, et al. Relative bioavailability and safety profile of gefitinib administered as a tablet or as a dispersion preparation via drink or nasogastric tube: results of a randomized, open-label, three-period crossover study in healthy volunteers. Clin Ther 2004; 26(10): 1630–36

    Article  PubMed  CAS  Google Scholar 

  54. Swaisland HC, Cantarini MV, Fuhr R, et al. Exploring the relationship between expression of cytochrome P450 enzymes and gefitinib pharmacokinetics. Clin Pharmacokinet 2006; 45(6): 633–44

    Article  PubMed  CAS  Google Scholar 

  55. Swaisland HC, Ranson M, Smith RP, et al. Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin Pharmacokinet 2005; 44(10): 1067–81

    Article  PubMed  CAS  Google Scholar 

  56. Chhun S, Verstuyft C, Rizzo-Padoin N, et al. Gefitinib-phenytoin interaction is not correlated with the C-erythromycin breath test in healthy male volunteers. Br J Clin Pharmacol 2009; 68(2): 226–37

    Article  PubMed  CAS  Google Scholar 

  57. Reardon DA, Quinn JA, Vredenburgh JJ, et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 2006; 12(3 Pt 1): 860–8

    Article  PubMed  CAS  Google Scholar 

  58. Adjei AA, Molina JR, Mandrekar SJ, et al. Phase I trial of sorafenib in combination with gefitinib in patients with refractory or recurrent non-small cell lung cancer. Clin Cancer Res 2007; 13(9): 2684–91

    Article  PubMed  CAS  Google Scholar 

  59. Li J, Karlsson MO, Brahmer J, et al. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. J Natl Cancer Inst 2006; 98(23): 1714–23

    Article  PubMed  CAS  Google Scholar 

  60. Ling J, Johnson KA, Miao Z, et al. Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug Metab Dispos 2006; 34(3): 420–6

    PubMed  CAS  Google Scholar 

  61. Frohna P, Lu J, Eppler S, et al. Evaluation of the absolute oral bioavailability and bioequivalence of erlotinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in a randomized, crossover study in healthy subjects. J Clin Pharmacol 2006; 46(3): 282–90

    Article  PubMed  CAS  Google Scholar 

  62. Lu JF, Eppler SM, Wolf J, et al. Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther 2006; 80(2): 136–45

    Article  PubMed  CAS  Google Scholar 

  63. Ling J, Fettner S, Lum BL, et al. Effect of food on the pharmacokinetics of erlotinib, an orally active epidermal growth factor receptor tyrosine-kinase inhibitor, in healthy individuals. Anticancer Drugs 2008; 19(2): 209–16

    Article  PubMed  CAS  Google Scholar 

  64. Ranson M, Shaw H, Wolf J, et al. A phase I dose-escalation and bioavailability study of oral and intravenous formulations of erlotinib (Tarceva, OSI-774) in patients with advanced solid tumors of epithelial origin. Cancer Chemother Pharmacol 2010; 66(1): 53–8

    Article  PubMed  CAS  Google Scholar 

  65. Rudin CM, Liu W, Desai A, et al. Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol 2008; 26(7): 1119–27

    Article  PubMed  CAS  Google Scholar 

  66. Tan AR, Yang X, Hewitt SM, et al. Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. J Clin Oncol 2004; 22(15): 3080–90

    Article  PubMed  CAS  Google Scholar 

  67. Yamamoto N, Horiike A, Fujisaka Y, et al. 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 2008; 61(3): 489–96

    Article  PubMed  CAS  Google Scholar 

  68. Hamilton M, Wolf JL, Rusk J, et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 2006; 12(7 Pt 1): 2166–71

    Article  PubMed  CAS  Google Scholar 

  69. Hughes AN, O’Brien ME, Petty WJ, et al. Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers. J Clin Oncol 2009; 27(8): 1220–6

    Article  PubMed  CAS  Google Scholar 

  70. Broniscer A, Baker SJ, Stewart CF, et al. Phase I and pharmacokinetic studies of erlotinib administered concurrently with radiotherapy for children, adolescents, and young adults with high-grade glioma. Clin Cancer Res 2009; 15(2): 701–7

    Article  PubMed  CAS  Google Scholar 

  71. Jakacki RI, Hamilton M, Gilbertson RG, et al. Pediatric phase I and pharmacokinetic study of erlotinib followed by the combination of erlotinib and temozolomide: a Children’s Oncology Group Phase I Consortium study. J Clin Oncol 2008; 26(30): 4921–7

    Article  PubMed  CAS  Google Scholar 

  72. Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of erlotinib for solid tumors in patients with hepatic or renal dysfunction: CALGB 60101. J Clin Oncol 2007; 25(21): 3055–60

    Article  PubMed  CAS  Google Scholar 

  73. Messersmith WA, Laheru DA, Senzer NN, et al. Phase I trial of irinotecan, infusional 5-fluorouracil, and leucovorin (FOLFIRI) with erlotinib (OSI-774): early termination due to increased toxicities. Clin Cancer Res 2004; 10(19): 6522–7

    Article  PubMed  CAS  Google Scholar 

  74. Herbst RS, Johnson DH, Mininberg E, et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005; 23(11): 2544–55

    Article  PubMed  CAS  Google Scholar 

  75. Van den Bent MJ, Brandes AA, Rampling R, et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC Brain Tumor Group study 26034. J Clin Oncol 2009; 27(8): 1268–74

    Article  PubMed  CAS  Google Scholar 

  76. Johnson JR, Cohen M, Sridhara R, et al. 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 2005; 11(18): 6414–21

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  78. Nakagawa K, Minami H, Kanezaki M, et al. Phase I dose-escalation and pharmacokinetic trial of lapatinib (GW572016), a selective oral dual inhibitor of ErbB-1 and -2 tyrosine kinases, in Japanese patients with solid tumors. Jpn J Clin Oncol 2009; 39(2): 116–23

    Article  PubMed  Google Scholar 

  79. Koch KM, Reddy NJ, Cohen RB, et al. Effects of food on the relative bioavailability of lapatinib in cancer patients. J Clin Oncol 2009; 27(8): 1191–6

    Article  PubMed  CAS  Google Scholar 

  80. Smith DA, Koch KM, Arya N, et al. Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects. Br J Clin Pharmacol 2009; 67(4): 421–6

    Article  PubMed  CAS  Google Scholar 

  81. Thiessen B, Stewart C, Tsao M, et al. A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation. Cancer Chemother Pharmacol 2010; 65(2): 353–61

    Article  PubMed  CAS  Google Scholar 

  82. Medina P, Goodin S. Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clinical Ther 2008; 30(8): 1426–47

    Article  CAS  Google Scholar 

  83. McKillop D, Hutchison M, Partridge EA, et al. Metabolic disposition of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat, dog and man. Xenobiotica 2004; 34(10): 917–34

    Article  PubMed  CAS  Google Scholar 

  84. McKillop D, McCormick AD, Millar A, et al. Cytochrome P450-dependent metabolism of gefitinib. Xenobiotica 2005; 35(1): 39–50

    Article  PubMed  CAS  Google Scholar 

  85. Jackman DM, Holmes AJ, Lindeman N, et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol 2006; 24(27): 4517–20

    Article  PubMed  Google Scholar 

  86. Hofer S, Frei K, Rutz HP. Gefitinib accumulation in glioblastoma tissue. Cancer Biol Ther 2006; 5(5): 483–4

    Article  PubMed  CAS  Google Scholar 

  87. Villano JL, Mauer AM, Vokes EE. A case study documenting the anticancer activity of ZD1839 (Iressa) in the brain. Ann Oncol 2003; 14(4): 656–8

    Article  PubMed  CAS  Google Scholar 

  88. Meany HJ, Fox E, McCully C, et al. The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates. Cancer Chemother Pharmacol 2008; 62(3): 387–92

    Article  PubMed  CAS  Google Scholar 

  89. Broniscer A, Panetta JC, O’Shaughnessy M, et al. Plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite OSI-420. Clin Cancer Res 2007; 13(5): 1511–5

    Article  PubMed  CAS  Google Scholar 

  90. Togashi Y, Masago K, Fukudo M, et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J Thorac Oncol 2010; 5(7): 950–5

    PubMed  Google Scholar 

  91. Porta R, Sánchez-Torres JM, Paz-Ares L, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J 2011 Mar;37(3): 624–31

    Article  PubMed  CAS  Google Scholar 

  92. Dhruva N, Socinski MA. Carcinomatous meningitis in non-small-cell lung cancer: response to high-dose erlotinib. J Clin Oncol 2009; 27(22): 31–2

    Article  Google Scholar 

  93. Rogers LR, Lorusso P, Nadler P, et al. Erlotinib therapy for central nervous system hemangioblastomatosis associated with von Hippel-Lindau disease: a case report. J Neurooncol 2011 Jan;101(2): 307–10

    Article  PubMed  Google Scholar 

  94. Polli JW, Olson KL, Chism JP, et al. An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-3-chloro-4-(3-fluorobenzyl)oxyphenyl-6-[5-([2-(methylsulfonyl)ethy l]aminomethyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos 2009; 37(2): 439–42

    Article  PubMed  CAS  Google Scholar 

  95. Gril B, Palmieri D, Bronder JL, et al. Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 2008; 100: 1092–103

    Article  PubMed  CAS  Google Scholar 

  96. Lin NU, Diéras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 2009; 15(4): 1452–9

    Article  PubMed  CAS  Google Scholar 

  97. Kremer JM, Wilting J, Janssen LH. Drug binding to human alpha-l-acid glycoprotein in health and disease. Pharmacol Rev 1988; 40(1): 1–47

    PubMed  CAS  Google Scholar 

  98. Gambacorti-Passerini C, Zucchetti M, Russo D, et al. Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 2003; 9(2): 625–32

    PubMed  CAS  Google Scholar 

  99. Baumann H, Gauldie J. The acute phase response. Immunol Today 1994; 15(2): 74–80

    Article  PubMed  CAS  Google Scholar 

  100. Fournier T, Medjoubi-N N, Porquet D. Alpha-1-acid glycoprotein. Biochim Biophys Acta 2000; 1482(1-2): 157–71

    Article  PubMed  CAS  Google Scholar 

  101. Israili ZH, Dayton PG. Human alpha-1-glycoprotein and its interactions with drugs. Drug Metab Rev 2001; 33(2): 161–235

    Article  PubMed  CAS  Google Scholar 

  102. Li J, Zhao M, He P, et al. Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res 2007; 13(12): 3731–7

    Article  PubMed  CAS  Google Scholar 

  103. Ward WH, Cook PN, Slater AM, et al. Epidermal growth factor receptor tyrosine kinase: investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem Pharmacol 1994; 48(4): 659–66

    Article  PubMed  CAS  Google Scholar 

  104. McKillop D, Guy SP, Spence MP, et al. Minimal contribution of desmethyl-gefitinib, the major human plasma metabolite of gefitinib, to epidermal growth factor receptor (EGFR)-mediated tumour growth inhibition. Xenobiotica 2006; 36(1): 29–39

    Article  PubMed  CAS  Google Scholar 

  105. Clark GM, Zborowski DM, Santabarbara P, et al.; National Cancer Institute of Canada Clinical Trials Group. Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21. Clin Lung Cancer 2006; 7(6): 389–94

    Article  PubMed  CAS  Google Scholar 

  106. Gridelli C, Maione P, Castaldo V, et al. Gefitinib in elderly and unfit patients affected by advanced non-small-cell lung cancer. Br J Cancer 2003; 89(10): 1827–9

    Article  PubMed  CAS  Google Scholar 

  107. Cappuzzo F, Bartolini S, Ceresoli GL, et al. Efficacy and tolerability of gefitinib in pretreated elderly patients with advanced non-small-cell lung cancer (NSCLC). Br J Cancer 2004; 90(1): 82–6

    Article  PubMed  CAS  Google Scholar 

  108. Ebi N, Semba H, Tokunaga SJ, et al. A phase II trial of gefitinib monotherapy in chemotherapy-naive patients of 75 years or older with advanced non-small cell lung cancer. J Thorac Oncol 2008; 3(10): 1166–71

    Article  PubMed  Google Scholar 

  109. Baselga J, Rischin D, Ranson M, et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002; 20(21): 4292–302

    Article  PubMed  CAS  Google Scholar 

  110. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350(21): 2129–39

    Article  PubMed  CAS  Google Scholar 

  111. Christiansen SR, Broniscer A, Panetta JC, et al. Pharmacokinetics of erlotinib for the treatment of high-grade glioma in a pediatric patient with cystic fibrosis: case report and review of the literature. Pharmacotherapy 2009; 29(7): 858–66

    Article  PubMed  CAS  Google Scholar 

  112. Wheatley-Price P, Ding K, Seymour L, et al. Erlotinib for advanced non-small-cell lung cancer in the elderly: an analysis of the National Cancer Institute of Canada Clinical Trials Group study BR.21. J Clin Oncol 2008; 26(14): 2350–7

    Article  PubMed  CAS  Google Scholar 

  113. Gorlick R, Anders Kolb E, Houghton PJ, et al. Initial testing (stage 1) of lapatinib by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2009; 53(4): 594–8

    Article  PubMed  Google Scholar 

  114. Ho C, Davis J, Anderson F, et al. Side effects related to cancer treatment: case 1. Hepatitis following treatment with gefitinib. J Clin Oncol 2005; 23(33): 8531–3

    Article  PubMed  Google Scholar 

  115. Carlini P, Papaldo P, Fabi A, et al. Liver toxicity after treatment with gefitinib and anastrozole: drug-drug interactions through cytochrome p450?. J Clin Oncol 2006; 24(35): 60–1

    Article  Google Scholar 

  116. Li X, Kamenecka TM, Cameron MD. Bioactivation of the epidermal growth factor receptor inhibitor gefitinib: implications for pulmonary and hepatic toxicities. Chem Res Toxicol 2009; 22(10): 1736–42

    Article  PubMed  CAS  Google Scholar 

  117. Ozvegy-Laczka C, Hegedus T, Varady G, et al. High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol 2004; 65(6): 1485–95

    Article  PubMed  Google Scholar 

  118. Nakamura Y, Oka M, Soda H, et al. Gefitinib (“Iressa”, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. Cancer Res 2005; 65(4): 1541–6

    Article  PubMed  CAS  Google Scholar 

  119. Li J, Cusatis G, Brahmer J, et al. Association of variant ABCG2 and the pharmacokinetics of epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients. Cancer Biol Ther 2007; 6(3): 432–8

    Article  PubMed  CAS  Google Scholar 

  120. Prados MD, Yung WK, Wen PY, et al. Phase-1 trial of gefitinib and temo-zolomide in patients with malignant glioma: a North American Brain Tumor Consortium study. Cancer Chemother Pharmacol 2008; 61(6): 1059–67

    Article  PubMed  CAS  Google Scholar 

  121. Flaherty KT, Redlinger M, Schuchter LM, et al. Phase I/II, pharmacokinetic and pharmacodynamic trial of BAY 43-9006 alone in patients with metastatic melanoma [abstract no. 3037]. Proc Am Soc Clin Oncol 2005; 23: 201s

    Google Scholar 

  122. Motzer RJ, Hudes GR, Ginsberg MS, et al. Phase I/II trial of sunitinib plus gefitinib in patients with metastatic renal cell carcinoma. Am J Clin Oncol 2010; 33(6): 614–8

    Article  PubMed  CAS  Google Scholar 

  123. Cantarini MV, Macpherson MP, Marshall AL, et al. A phase I study to determine the effect of tamoxifen on the pharmacokinetics of a single 250mg oral dose of gefitinib (Iressa) in healthy male volunteers. Cancer Chemother Pharmacol 2005; 56(6): 557–62

    Article  PubMed  CAS  Google Scholar 

  124. Milton DT, Riely GJ, Azzoli CG, et al. Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer 2007; 110(3): 599–605

    Article  PubMed  CAS  Google Scholar 

  125. Miller VA, Johnson DH, Krug LM, et al. Pilot trial of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib plus carboplatin and pac-litaxel in patients with stage IIIB or IV non-small-cell lung cancer. J Clin Oncol 2003; 21(11): 2094–100

    Article  PubMed  CAS  Google Scholar 

  126. O’Byrne KJ, Danson S, Dunlop D, et al. Combination therapy with gefitinib and rofecoxib in patients with platinum-pretreated relapsed non small-cell lung cancer. J Clin Oncol 2007; 25(22): 3266–73

    Article  PubMed  CAS  Google Scholar 

  127. Giaccone G, Gonza’lez-Larriba JL, van Oosterom AT, et al. Combination therapy with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, gemcitabine and cisplatin in patients with advanced solid tumors. Ann Oncol 2004; 15(5): 831–8

    Article  PubMed  CAS  Google Scholar 

  128. Fakih MG, Trump DL, Muindi JR, et al. A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors. Clin Cancer Res 2007; 13(4): 1216–23

    Article  PubMed  CAS  Google Scholar 

  129. Meyerhardt JA, Clark JW, Supko JG, et al. Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer. Cancer Chemother Pharmacol 2007; 60(5): 661–70

    Article  PubMed  CAS  Google Scholar 

  130. Fujita K, Ando Y, Narabayashi M, et al. Gefitinib (Iressa) inhibits the CYP3A4-mediated formation of 7-ethyl-10-(4-amino-1-piperidino)carbonylox-ycamptothecin but activates that of 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin from irinotecan. Drug Metab Dispos 2005; 33(12): 1785–90

    PubMed  CAS  Google Scholar 

  131. Wilding G, Soulie P, Trump D, et al. Results from a pilot phase I trial of gefitinib combined with docetaxel and estramustine in patients with hormone-refractory prostate cancer. Cancer 2006; 106(9): 1917–24

    Article  PubMed  CAS  Google Scholar 

  132. Sumitomo M, Asano T, Asakuma J, et al. ZD1839 modulates paclitaxel response in renal cancer by blocking paclitaxel-induced activation of the epidermal growth factor receptor-extracellular signal-regulated kinase pathway. Clin Cancer Res 2004; 10(2): 794–801

    Article  PubMed  CAS  Google Scholar 

  133. Hwang SW, Han HS, Lim KY, et al. Drug interaction between complementary herbal medicines and gefitinib. J Thorac Oncol 2008; 3(8): 942–3

    Article  PubMed  Google Scholar 

  134. Kuang YH, Shen T, Chen X, et al. Lapatinib and erlotinib are potent reversal agents for MRP7(ABCC10)-mediated multidrug resistance. Biochem Pharmacol 2010; 79(2): 154–61

    Article  PubMed  CAS  Google Scholar 

  135. Abbas R, Fettner S, Riek M, et al. A drug-drug interaction study to evaluate the effect of rifampicin on the pharmacokinetics of the EGF receptor tyro-sine kinase inhibitor, erlotinib, in healthy subjects [abstract]. Proc Am Soc Clin Oncol 2003; 22: 548

    Google Scholar 

  136. Rakhit A, Pantze MP, Fettner S, et al. The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition. Eur J Clin Pharmacol 2008; 64(1): 31–41

    Article  PubMed  CAS  Google Scholar 

  137. Patnaik A, Wood D, Tolcher AW, et al. Phase I, pharmacokinetic, and biological study of erlotinib in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Clin Cancer Res 2006; 12(24): 7406–13

    Article  PubMed  CAS  Google Scholar 

  138. Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007; 25(12): 1545–52

    Article  PubMed  CAS  Google Scholar 

  139. Duran I, Hotté SJ, Hirte H, et al. Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors. Clin Cancer Res 2007; 13(16): 4849–57

    Article  PubMed  CAS  Google Scholar 

  140. Chiorean EG, Porter JM, Foster AE, et al. A phase I and pharmacokinetic trial of erlotinib in combination with weekly docetaxel in patients with taxane-naive malignancies. Clin Cancer Res 2008; 14(4): 1131–7

    Article  PubMed  CAS  Google Scholar 

  141. Ranson M, Reck M, Anthoney A, et al. Erlotinib in combination with pemetrexed for patients with advanced non-small-cell lung cancer (NSCLC): a phase I dose-finding study. Ann Oncol 2010; 21(11): 2233–9

    Article  PubMed  CAS  Google Scholar 

  142. Takakusa H, Wahlin MD, Zhao C, et al. Metabolic-intermediate complex formation of human cytochrome P450 3A4 by lapatinib. Drug Metab Dispos. Epub 2011 Mar 1

  143. Dunne G, Breen L, Collins DM, et al. Modulation of P-gp expression by lapatinib. Invest New Drugs. Epub 2010 Jul 6

  144. Collins DM, Crown J, O’Donovan N, et al. Tyrosine kinase inhibitors potentiate the cytotoxicity of MDR-substrate anticancer agents independent of growth factor receptor status in lung cancer cell lines. Invest New Drugs 2010; 28(4): 433–44

    Article  PubMed  CAS  Google Scholar 

  145. Deeken JF, Pantanowitz L, Dezube BJ. Targeted therapies to treat non-AIDS-defining cancers in patients with HIV on HAART therapy: treatment considerations and research outlook. Curr Opin Oncol 2009; 21: 445–54

    Article  PubMed  CAS  Google Scholar 

  146. Midgley RS, Kerr DJ, Flaherty KT, et al. A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan. Ann Oncol 2007; 18: 2025–9

    Article  PubMed  CAS  Google Scholar 

  147. Siegel-Lakhai WS, Beijnen JH, Vervenne WL, et al. Phase I pharmacokinetic study of the safety and tolerability of lapatinib (GW572016) in combination with oxaliplatin/fluorouracil/leucovorin (FOLFOX4) in patients with solid tumors. Clin Cancer Res 2007; 13(15): 4495–502

    Article  PubMed  CAS  Google Scholar 

  148. Storniolo AM, Pegram MD, Overmoyer B, et al. Phase I dose escalation and pharmacokinetic study of lapatinib in combination with trastuzumab in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 2008; 26(20): 3317–23

    Article  PubMed  CAS  Google Scholar 

  149. Lo Russo PM, Jones SF, Koch KM, et al. Phase I and pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer. J Clin Oncol 2008; 26: 3051–6

    Article  CAS  Google Scholar 

  150. Chu QSC, Cianfrocca ME, Goldstein LJ, et al. A phase I and pharmacokinetic study of lapatinib in combination with letrozole in patients with advanced cancer. Clin Cancer Res 2008; 14(14): 4484–90

    Article  PubMed  CAS  Google Scholar 

  151. Minematsu T, Giacomini KM. Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther 2011; 10(3): 531–9

    Article  PubMed  CAS  Google Scholar 

  152. Cusatis G, Sparreboom A. Pharmacogenomic importance of ABCG2. Pharmacogenomics 2008; 9(8): 1005–9

    Article  PubMed  CAS  Google Scholar 

  153. Shi Z, Peng XX, Kim IW, et al. Erlotinib (Tarceva, OSI-774) antagonizes ATP binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance. Cancer Res 2007; 67(22): 11012–20

    Article  PubMed  CAS  Google Scholar 

  154. Marchetti S, de Vries NA, Buckle T, et al. Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/-(triple-knockout) and wild-type mice. Mol Cancer Ther 2008; 7(8): 2280–7

    Article  PubMed  CAS  Google Scholar 

  155. Wolf M, Swaisland H, Averbuch S. Development of the novel biologically targeted anticancer agent gefitinib: determining the optimum dose for clinical efficacy. Clin Cancer Res 2004; 10(14): 4607–13

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No source of funding was used to assist in the preparation of this review. In adherence to the guidelines of the International Committee of Medical Journal Editors, no conflict of interest is to be declared.

Author information

Authors and Affiliations

  1. 1st Department of Internal Medicine, Lung Cancer Group Cologne, Cologne, Germany

    Matthias Scheffler & Jürgen Wolf

  2. Clinical Pharmacology Unit, Department of Pharmacology, University Hospital, University of Cologne, Cologne, Germany

    Paola Di Gion, Oxana Doroshyenko &  Uwe Fuhr

Authors
  1. Matthias Scheffler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Di Gion
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oxana Doroshyenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jürgen Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Uwe Fuhr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Uwe Fuhr.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Scheffler, M., Di Gion, P., Doroshyenko, O. et al. Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors. Clin Pharmacokinet 50, 371–403 (2011). https://doi.org/10.2165/11587020-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11587020-000000000-00000

Keywords

Search

Navigation