Letters to the Editor / Lung Cancer 86 (2014) 112–114
113
Sevasti Koumiotaki Department of Respiratory Medicine, General Hospital of Heraklion - ‘Venizelio’ Crete, Greece Nikolaos Androulakis Medical Oncology Unit, General Hospital of Heraklion - ‘Venizelio’, Crete, Greece Vassilis Georgoulias Department of Medical Oncology, University Hospital of Heraklion, Crete, Greece ∗ Corresponding
author at: Medical Oncology Unit, General Hospital of Heraklion - ‘Venizelio’, P.O. Box 44, 71409 Heraklion, Crete, Greece. Tel.: +30 2810 368158; fax: +30 2810 368053. E-mail address: [email protected] (E. Saloustros) 19 February 2014
http://dx.doi.org/10.1016/j.lungcan.2014.07.016
High exposure to erlotinib and severe druginduced interstitial lung disease in patients with non-small-cell lung cancer Keywords: Erlotinib Interstitial lung disease Pharmacokinetics High exposure ABCG2 Polymorphism
Erlotinib is a potent epidermal growth factor receptor tyrosine kinase inhibitor that is widely used to treat advanced nonsmall-cell lung cancer (NSCLC) [1]. Orally administered erlotinib shows large interindividual variability in its pharmacokinetics [2]. Although infrequent, severe and occasionally fatal interstitial lung disease (ILD) has been reported in patients who received erlotinib, and a relation between high plasma erlotinib concentrations and the development of ILD has been suggested [2]. Erlotinib is excreted into bile by ATP-binding cassette subfamily G member 2 (ABCG2). The natural allelic variant ABCG2 421C>A, which is associated with the decreased protein expression, has been linked to reduced clearance of erlotinib [2] and may thus be the underlying cause of severe erlotinib-induced pneumonia. We prospectively evaluated toxic effects and pharmacokinetics of erlotinib, and ABCG2 421C>A status in 25 patients with NSCLC (18 men and 7 women; median age 68 years, range 31–82) who received erlotinib in a dose of 150 mg once daily. Adverse events were classified according to the Common Terminology Criteria for Adverse Events, version. 4.0. Plasma erlotinib concentrations right before the erlotinib administration and 1, 2, 4, 8, and 24 h after the administration on day 1, and trough concentration (C0 ) on day 8 were analyzed by high-performance liquid chromatography as described by Faivre et al. [3], except that we used an Inertsil C8-3 analytical column (3.0 mm × 250 mm; 5 m; GL Sciences, Tokyo, Japan). The ABCG2 polymorphism was determined by direct sequencing. All patients gave written informed consent approved by the Institutional Review Board of Showa University. Among 25 patients evaluated, 3 patients suffered from severe ILD (≥ grade 4) within 8 days of erlotinib initiation. Especially, a 73-year-old man (patient A) had fatal erlotinib-related ILD with ground-glass opacity in the right lower lobe on day 7. Although erlotinib was immediately discontinued and corticosteroid pulse therapy administered, there was no improvement in respiratory
Fig. 1. Pharmacokinetics of erlotinib observed in 25 patients with NSCLC. Twentyfive patients with NSCLC received erlotinib in a dose of 150 mg once daily. Plasma erlotinib concentrations right before the erlotinib administration and 1, 2, 4, 8, and 24 h after the administration on day 1. Chain dashed line, patient A; chain double dashed line, patient B; dotted line, patient C.
failure, and the patient died of an acute exacerbation of ILD several days later. The other 78- and 80-year-old female patients (patients B and C) suffered from grade 4 ILD on day 7 and 8, respectively. The pharmacokinetic profiles of erlotinib on day 1 in 25 patients are shown in Fig. 1. The median area under the plasma concentration–time curve of erlotinib estimated from 0 to 24 h (AUC0–24 ) was 69.1 (range, 35.5–123) M h. The patients A and B showed the highest and the third highest erlotinib AUC0–24 (123 and 112 M h, respectively). Although patient C showed the lowest AUC0–24 (35.5 M h), the plasma concentration continuously increased after the erlotinib administration, and the maximum plasma concentration in patient C was observed at 24 h after the erlotinib administration (dotted line in Fig. 1). This atypical erlotinib pharmacokinetics in patient C resulted in the accumulation of erlotinib and the C0 on day 8 in this patient was the third highest (8.20 M) among patients examined (median 5.84 (range 3.51–8.33) M, n = 21). C0 values on day 8 were not available for patients A and B because of the onset of ILD on day 7. Our pharmacogenetic analysis revealed that the patient A was homozygous for ABCG2 C>A. Patients homozygous for ABCG2 C>A might have decreased elimination of erlotinib [2], resulting in very high exposure to the drug, potentially leading to fatal ILD. These results suggest that the high exposure to erlotinib, which is possibly related to functional ABCG2 polymorphism, makes patients prone to suffer from drug-induced severe ILD. The allele frequency of ABCG2 C>A in Japanese (∼30%) is higher than that in whites (∼10%) [4]. This difference might be related to higher incidence of ILD-like events in Japanese patients (∼5%) [5] than in patients in the United States (∼1%) [6]. However, the susceptibility to the adverse reaction must be determined not only by pharmacokinetics but also by toxicological properties of the drug. To date, unfortunately, underlying toxicological mechanism for the erlotinib-induced ILD was not fully elucidated. Further systematic studies are warranted to clarify these critical issues. Conflict of interest The authors have no conflict of interest to declare. Acknowledgements This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan [23-A-16 to YS]; and in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS) [23590648 to TH].
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Letters to the Editor / Lung Cancer 86 (2014) 112–114
References [1] Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32. [2] Fukudo M, Ikemi Y, Togashi Y, Masago K, Kim YH, Mio T, 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 2013;52:593–609. [3] Faivre L, Gomo C, Mir O, Taieb F, Schoemann-Thomas A, Ropert S, et al. A simple HPLC-UV method for the simultaneous quantification of gefitinib and erlotinib in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2011;879:2345–50. [4] Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet 2012;27:9–54. [5] Kubota K, Nishiwaki Y, Tamura T, Nakagawa K, Matsui K, Watanabe K, et al. Efficacy and safety of erlotinib monotherapy for Japanese patients with advanced non-small cell lung cancer: a phase II study. J Thorac Oncol 2008;3:1439–45. [6] Astellas Highlights of prescribing information (erlotinib). http://www. [accessed accessdata.fda.gov/drugsatfda docs/label/2013/021743s018lbl.pdf 19.6.14].
Ken-ichi Fujita a,b,∗ Department of Medical Oncology, International Medical Center-Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan b Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Tokyo 142-8555, Japan a
Hirose a,b
Takashi a Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Tokyo 142-8666, Japan b Department of Respirology, National Hospital Organization, Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, Tokyo 204-8585, Japan
Sojiro Kusumoto Tomohide Sugiyama Takao Shirai Masanao Nakashima Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Tokyo 142-8666, Japan Yuko Akiyama Department of Medical Oncology, International Medical Center-Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan Yasutsuna Sasaki a,b,c Department of Medical Oncology, International Medical Center-Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan b Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Tokyo 142-8555, Japan c Department of Medical Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Tokyo 142-8666, Japan a
∗ Corresponding
author at: Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Tokyo 142-8555, Japan. Tel.: +81 33784 8146; fax: +81 33784 2299. E-mail address: [email protected] (K.-i. Fujita) 3 July 2014
http://dx.doi.org/10.1016/j.lungcan.2014.07.021
113
Sevasti Koumiotaki Department of Respiratory Medicine, General Hospital of Heraklion - ‘Venizelio’ Crete, Greece Nikolaos Androulakis Medical Oncology Unit, General Hospital of Heraklion - ‘Venizelio’, Crete, Greece Vassilis Georgoulias Department of Medical Oncology, University Hospital of Heraklion, Crete, Greece ∗ Corresponding
author at: Medical Oncology Unit, General Hospital of Heraklion - ‘Venizelio’, P.O. Box 44, 71409 Heraklion, Crete, Greece. Tel.: +30 2810 368158; fax: +30 2810 368053. E-mail address: [email protected] (E. Saloustros) 19 February 2014
http://dx.doi.org/10.1016/j.lungcan.2014.07.016
High exposure to erlotinib and severe druginduced interstitial lung disease in patients with non-small-cell lung cancer Keywords: Erlotinib Interstitial lung disease Pharmacokinetics High exposure ABCG2 Polymorphism
Erlotinib is a potent epidermal growth factor receptor tyrosine kinase inhibitor that is widely used to treat advanced nonsmall-cell lung cancer (NSCLC) [1]. Orally administered erlotinib shows large interindividual variability in its pharmacokinetics [2]. Although infrequent, severe and occasionally fatal interstitial lung disease (ILD) has been reported in patients who received erlotinib, and a relation between high plasma erlotinib concentrations and the development of ILD has been suggested [2]. Erlotinib is excreted into bile by ATP-binding cassette subfamily G member 2 (ABCG2). The natural allelic variant ABCG2 421C>A, which is associated with the decreased protein expression, has been linked to reduced clearance of erlotinib [2] and may thus be the underlying cause of severe erlotinib-induced pneumonia. We prospectively evaluated toxic effects and pharmacokinetics of erlotinib, and ABCG2 421C>A status in 25 patients with NSCLC (18 men and 7 women; median age 68 years, range 31–82) who received erlotinib in a dose of 150 mg once daily. Adverse events were classified according to the Common Terminology Criteria for Adverse Events, version. 4.0. Plasma erlotinib concentrations right before the erlotinib administration and 1, 2, 4, 8, and 24 h after the administration on day 1, and trough concentration (C0 ) on day 8 were analyzed by high-performance liquid chromatography as described by Faivre et al. [3], except that we used an Inertsil C8-3 analytical column (3.0 mm × 250 mm; 5 m; GL Sciences, Tokyo, Japan). The ABCG2 polymorphism was determined by direct sequencing. All patients gave written informed consent approved by the Institutional Review Board of Showa University. Among 25 patients evaluated, 3 patients suffered from severe ILD (≥ grade 4) within 8 days of erlotinib initiation. Especially, a 73-year-old man (patient A) had fatal erlotinib-related ILD with ground-glass opacity in the right lower lobe on day 7. Although erlotinib was immediately discontinued and corticosteroid pulse therapy administered, there was no improvement in respiratory
Fig. 1. Pharmacokinetics of erlotinib observed in 25 patients with NSCLC. Twentyfive patients with NSCLC received erlotinib in a dose of 150 mg once daily. Plasma erlotinib concentrations right before the erlotinib administration and 1, 2, 4, 8, and 24 h after the administration on day 1. Chain dashed line, patient A; chain double dashed line, patient B; dotted line, patient C.
failure, and the patient died of an acute exacerbation of ILD several days later. The other 78- and 80-year-old female patients (patients B and C) suffered from grade 4 ILD on day 7 and 8, respectively. The pharmacokinetic profiles of erlotinib on day 1 in 25 patients are shown in Fig. 1. The median area under the plasma concentration–time curve of erlotinib estimated from 0 to 24 h (AUC0–24 ) was 69.1 (range, 35.5–123) M h. The patients A and B showed the highest and the third highest erlotinib AUC0–24 (123 and 112 M h, respectively). Although patient C showed the lowest AUC0–24 (35.5 M h), the plasma concentration continuously increased after the erlotinib administration, and the maximum plasma concentration in patient C was observed at 24 h after the erlotinib administration (dotted line in Fig. 1). This atypical erlotinib pharmacokinetics in patient C resulted in the accumulation of erlotinib and the C0 on day 8 in this patient was the third highest (8.20 M) among patients examined (median 5.84 (range 3.51–8.33) M, n = 21). C0 values on day 8 were not available for patients A and B because of the onset of ILD on day 7. Our pharmacogenetic analysis revealed that the patient A was homozygous for ABCG2 C>A. Patients homozygous for ABCG2 C>A might have decreased elimination of erlotinib [2], resulting in very high exposure to the drug, potentially leading to fatal ILD. These results suggest that the high exposure to erlotinib, which is possibly related to functional ABCG2 polymorphism, makes patients prone to suffer from drug-induced severe ILD. The allele frequency of ABCG2 C>A in Japanese (∼30%) is higher than that in whites (∼10%) [4]. This difference might be related to higher incidence of ILD-like events in Japanese patients (∼5%) [5] than in patients in the United States (∼1%) [6]. However, the susceptibility to the adverse reaction must be determined not only by pharmacokinetics but also by toxicological properties of the drug. To date, unfortunately, underlying toxicological mechanism for the erlotinib-induced ILD was not fully elucidated. Further systematic studies are warranted to clarify these critical issues. Conflict of interest The authors have no conflict of interest to declare. Acknowledgements This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan [23-A-16 to YS]; and in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS) [23590648 to TH].
114
Letters to the Editor / Lung Cancer 86 (2014) 112–114
References [1] Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32. [2] Fukudo M, Ikemi Y, Togashi Y, Masago K, Kim YH, Mio T, 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 2013;52:593–609. [3] Faivre L, Gomo C, Mir O, Taieb F, Schoemann-Thomas A, Ropert S, et al. A simple HPLC-UV method for the simultaneous quantification of gefitinib and erlotinib in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2011;879:2345–50. [4] Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet 2012;27:9–54. [5] Kubota K, Nishiwaki Y, Tamura T, Nakagawa K, Matsui K, Watanabe K, et al. Efficacy and safety of erlotinib monotherapy for Japanese patients with advanced non-small cell lung cancer: a phase II study. J Thorac Oncol 2008;3:1439–45. [6] Astellas Highlights of prescribing information (erlotinib). http://www. [accessed accessdata.fda.gov/drugsatfda docs/label/2013/021743s018lbl.pdf 19.6.14].
Ken-ichi Fujita a,b,∗ Department of Medical Oncology, International Medical Center-Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan b Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Tokyo 142-8555, Japan a
Hirose a,b
Takashi a Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Tokyo 142-8666, Japan b Department of Respirology, National Hospital Organization, Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, Tokyo 204-8585, Japan
Sojiro Kusumoto Tomohide Sugiyama Takao Shirai Masanao Nakashima Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Tokyo 142-8666, Japan Yuko Akiyama Department of Medical Oncology, International Medical Center-Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan Yasutsuna Sasaki a,b,c Department of Medical Oncology, International Medical Center-Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan b Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Tokyo 142-8555, Japan c Department of Medical Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Tokyo 142-8666, Japan a
∗ Corresponding
author at: Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Tokyo 142-8555, Japan. Tel.: +81 33784 8146; fax: +81 33784 2299. E-mail address: [email protected] (K.-i. Fujita) 3 July 2014
http://dx.doi.org/10.1016/j.lungcan.2014.07.021
