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Population Pharmacokinetics/Pharmacodynamics of Erlotinib and Pharmacogenomic Analysis of Plasma and Cerebrospinal Fluid Drug Concentrations in Japanese Patients with Non-Small Cell Lung Cancer

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Abstract

Background

Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420.

Methods

A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236C>T, 2677G>T/A, 3435C>T), ABCG2 (421C>A), and CYP3A5 (6986A>G) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated.

Results

The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p < 0.001), while ABCB1 and CYP3A5 polymorphisms did not affect their apparent clearance. The ABCG2 421A allele was significantly associated with increased CSF penetration for both erlotinib and OSI-420 (p < 0.05). Furthermore, the incidence of grade ≥2 diarrhea was significantly higher in patients harboring this mutant allele (p = 0.035). A multivariate logistic regression model showed that erlotinib trough (C0) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C0 levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C0 levels (≥1711 ng/mL) than that in patients having lower erlotinib C0 levels (38 versus 5 %; p = 0.058), whereas no greater response was observed in the higher group (67 %) versus the lower group (77 %) within EGFR mutation-positive patients (p = 0.62).

Conclusions

ABCG2 can influence the apparent clearance of erlotinib and OSI-420, and their CSF permeabilities in patients with NSCLC. Our preliminary findings indicate that early exposure to erlotinib may be associated with the development of adverse events and that increased erlotinib exposure may be relevant to the antitumor effects in EGFR wild-type patients while having less of an impact on the tumor response in EGFR mutation-positive patients.

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References

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

    Google Scholar 

  2. 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;80:136–45.

    Article  PubMed  CAS  Google Scholar 

  3. Thomas F, Rochaix P, White-Koning M, et al. Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma. Eur J Cancer. 2009;45:2316–23.

    Article  PubMed  CAS  Google Scholar 

  4. White-Koning M, Civade E, Geoerger B, et al. Population analysis of erlotinib in adults and children reveals pharmacokinetic characteristics as the main factor explaining tolerance particularities in children. Clin Cancer Res. 2011;17:4862–71.

    Article  PubMed  CAS  Google Scholar 

  5. Hotta K, Kiura K, Takigawa N, et al. Comparison of the incidence and pattern of interstitial lung disease during erlotinib and gefitinib treatment in Japanese patients with non-small cell lung cancer: the Okayama Lung Cancer Study Group experience. J Thorac Oncol. 2010;5:179–84.

    Article  PubMed  Google Scholar 

  6. Tamura T, Nishiwaki Y, Watanabe K, et al. Evaluation of efficacy and safety of erlotinib as monotherapy for Japanese patients with advanced non-small cell lung cancer (NSCLC); integrated analysis of two Japanese phase II studies. J Thorac Oncol. 2007;2(Suppl 4):S742–3.

    Article  Google Scholar 

  7. Togashi Y, Masago K, Mishima M, et al. A case of radiation recall pneumonitis induced by erlotinib, which can be related to high plasma concentration. J Thorac Oncol. 2010;5:924–5.

    Article  PubMed  Google Scholar 

  8. Tsubata Y, Hamada A, Sutani A, et al. Erlotinib-induced acute interstitial lung disease associated with extreme elevation of the plasma concentration in an elderly non-small-cell lung cancer patient. J Cancer Res Ther. 2012;8:154–6.

    Article  PubMed  Google Scholar 

  9. ter Heine R, van den Bosch RT, Schaefer-Prokop CM, et al. Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature. Lung Cancer. 2012;75:391–7.

    Article  PubMed  Google Scholar 

  10. 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;34:420–6.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27:383–91.

    Article  PubMed  CAS  Google Scholar 

  13. 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;98:1714–23.

    Article  PubMed  CAS  Google Scholar 

  14. 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;7:2280–7.

    Article  PubMed  CAS  Google Scholar 

  15. Hamada A, Sasaki J, Saeki S, et al. Association of ABCB1 polymorphisms with erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer. Pharmacogenomics. 2012;13:615–24.

    Article  PubMed  CAS  Google Scholar 

  16. Imai Y, Nakane M, Kage K, et al. C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. Mol Cancer Ther. 2002;1:611–6.

    PubMed  CAS  Google Scholar 

  17. de Jong FA, Marsh S, Mathijssen RH, et al. ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition. Clin Cancer Res. 2004;10:5889–94.

    Article  PubMed  Google Scholar 

  18. Mizuno T, Terada T, Kamba T, et al. ABCG2 421C>A polymorphism and high exposure of sunitinib in a patient with renal cell carcinoma. Ann Oncol. 2010;21:1382–3.

    Article  PubMed  CAS  Google Scholar 

  19. 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;6:432–8.

    Article  PubMed  CAS  Google Scholar 

  20. Clarke JL, Pao W, Wu N, et al. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol. 2010;99:283–6.

    Article  PubMed  Google Scholar 

  21. Togashi Y, Masago K, Masuda S, et al. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 2012;70:399–405.

    Article  PubMed  CAS  Google Scholar 

  22. Elmeliegy MA, Carcaboso AM, Tagen M, et al. Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation. Clin Cancer Res. 2011;17:89–99.

    Article  PubMed  CAS  Google Scholar 

  23. Lazarowski A, Czornyj L, Lubienieki F, et al. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia. 2007;48(Suppl 5):140–9.

    Article  PubMed  CAS  Google Scholar 

  24. 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;350:2129–39.

    Article  PubMed  CAS  Google Scholar 

  25. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.

    Article  PubMed  CAS  Google Scholar 

  26. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med. 2005;353:133–44.

    Article  PubMed  CAS  Google Scholar 

  27. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.

    Article  PubMed  CAS  Google Scholar 

  28. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–8.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  30. Morita S, Okamoto I, Kobayashi K, et al. Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations. Clin Cancer Res. 2009;15:4493–8.

    Article  PubMed  CAS  Google Scholar 

  31. Miller VA, Riely GJ, Zakowski MF, et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol. 2008;26:1472–8.

    Article  PubMed  CAS  Google Scholar 

  32. Paz-Ares L, Soulières D, Melezínek I, et al. Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: pooled analysis. J Cell Mol Med. 2010;14:51–69.

    Article  PubMed  CAS  Google Scholar 

  33. Yoshioka H, Hotta K, Kiura K, et al. A phase II trial of erlotinib monotherapy in pretreated patients with advanced non-small cell lung cancer who do not possess active EGFR mutations: Okayama Lung Cancer Study Group trial 0705. J Thorac Oncol. 2010;5:99–104.

    Article  PubMed  Google Scholar 

  34. Kobayashi T, Koizumi T, Agatsuma T, et al. A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 2012;69:1241–6.

    Article  PubMed  CAS  Google Scholar 

  35. Nakamura Y, Sano K, Soda H, et al. Pharmacokinetics of gefitinib predicts antitumor activity for advanced non-small cell lung cancer. J Thorac Oncol. 2010;5:1404–9.

    Article  PubMed  Google Scholar 

  36. Phan VH, Tan C, Rittau A, et al. An update on ethnic differences in drug metabolism and toxicity from anti-cancer drugs. Expert Opin Drug Metab Toxicol. 2011;7:1395–410.

    Article  PubMed  CAS  Google Scholar 

  37. Uesugi M, Masuda S, Katsura T, et al. Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients. Pharmacogenet Genomics. 2006;16:119–27.

    Article  PubMed  CAS  Google Scholar 

  38. Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther. 2001;69:169–74.

    Article  PubMed  CAS  Google Scholar 

  39. Nagai Y, Miyazawa H, Huqun, et al. Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res. 2005;65:7276–82.

  40. 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;814:143–7.

    Article  PubMed  CAS  Google Scholar 

  41. Beal SL, Sheiner LB. NONMEM User’s Guide. San Francisco: University of California; 1992.

  42. Hamilton M, Wolf JL, Rusk J, et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006;12:2166–71.

    Article  PubMed  CAS  Google Scholar 

  43. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  PubMed  CAS  Google Scholar 

  44. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.

    Article  Google Scholar 

  45. Kraut EH, Rhoades C, Zhang Y, et al. Phase I and pharmacokinetic study of erlotinib (OSI-774) in combination with docetaxel in squamous cell carcinoma of the head and neck (SSCHN). Cancer Chemother Pharmacol. 2011;67:579–86.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. Dong PP, Fang ZZ, Zhang YY, et al. Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib. Acta Pharmacol Sin. 2011;32:399–407.

    Article  PubMed  CAS  Google Scholar 

  48. Lind JS, Dingemans AM, Groen HJ, et al. A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer. Clin Cancer Res. 2010;16:3078–87.

    Article  PubMed  CAS  Google Scholar 

  49. Budha NR, Frymoyer A, Smelick GS, et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther. 2012;92:203–13.

    Article  PubMed  CAS  Google Scholar 

  50. Moreau C, Debray D, Loriot MA, et al. Interaction between tacrolimus and omeprazole in a pediatric liver transplant recipient. Transplantation. 2006;81:487–8.

    Article  PubMed  Google Scholar 

  51. Breedveld P, Pluim D, Cipriani G, et al. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res. 2005;65:2577–82.

    Article  PubMed  CAS  Google Scholar 

  52. Kim YH, Masago K, Mishima M. Erlotinib and gastrointestinal ulcer. J Thorac Oncol. 2010;5:1108–9.

    Article  PubMed  Google Scholar 

  53. Zhao J, Chen M, Zhong W, et al. Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. Clin Lung Cancer. 2013;14(2):188–93.

    Google Scholar 

  54. Chen YJ, Huang WC, Wei YL, et al. Elevated BCRP/ABCG2 expression confers acquired resistance to gefitinib in wild-type EGFR-expressing cells. PLoS One. 2011;6:e21428.

    Article  PubMed  CAS  Google Scholar 

  55. Cohen MH, Johnson JR, Chen YF, et al. FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist. 2005;10:461–6.

    Article  PubMed  CAS  Google Scholar 

  56. Boudou-Rouquette P, Narjoz C, Golmard JL, et al. Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study. PLoS One. 2012;7:e42875.

    Article  PubMed  CAS  Google Scholar 

  57. Cusatis G, Gregorc V, Li J, et al. Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. J Natl Cancer Inst. 2006;98:1739–42.

    Article  PubMed  CAS  Google Scholar 

  58. van Erp NP, Eechoute K, van der Veldt AA, et al. Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol. 2009;27:4406–12.

    Article  PubMed  Google Scholar 

  59. van der Veldt AA, Eechoute K, Gelderblom H, et al. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res. 2011;17:620–9.

    Article  PubMed  Google Scholar 

  60. Garcia-Donas J, Esteban E, Leandro-García LJ, et al. Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol. 2011;12:1143–50.

    Article  PubMed  CAS  Google Scholar 

  61. Yeo WL, Riely GJ, Yeap BY, et al. Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations. J Thorac Oncol. 2010;5:1048–53.

    PubMed  Google Scholar 

  62. Togashi Y, Masago K, Fujita S, et al. Differences in adverse events between 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer. Lung Cancer. 2011;74:98–102.

    Article  PubMed  Google Scholar 

  63. Pérez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol. 2004;22:3238–47.

    Article  PubMed  Google Scholar 

  64. Mita AC, Papadopoulos K, de Jonge MJ, et al. Erlotinib ‘dosing-to-rash’: a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer. Br J Cancer. 2011;105:938–44.

    Article  PubMed  CAS  Google Scholar 

  65. Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109:3496–9.

    Article  PubMed  CAS  Google Scholar 

  66. Guilhot F, Hughes TP, Cortes J, et al. Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial. Haematologica. 2012;97:731–8.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, by a Grant-in-Aid from the Fujiwara Memorial Foundation, and by a Grant-in-Aid from the Nakatomi Foundation. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan

    Masahide Fukudo, Yasuaki Ikemi, Tomohiro Terada, Ken-ichi Inui & Toshiya Katsura

  2. Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Yosuke Togashi, Katsuhiro Masago, Young Hak Kim, Tadashi Mio & Michiaki Mishima

  3. Department of Clinical Trial Design and Management, Translational Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Satoshi Teramukai

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  1. Masahide Fukudo
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Correspondence to Masahide Fukudo.

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Fukudo, M., Ikemi, Y., Togashi, Y. et al. Population Pharmacokinetics/Pharmacodynamics of Erlotinib and Pharmacogenomic Analysis of Plasma and Cerebrospinal Fluid Drug Concentrations in Japanese Patients with Non-Small Cell Lung Cancer. Clin Pharmacokinet 52, 593–609 (2013). https://doi.org/10.1007/s40262-013-0058-5

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