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ANALYTICAL REPORT
Year : 2012  |  Volume : 8  |  Issue : 1  |  Page : 154-156

Erlotinib-induced acute interstitial lung disease associated with extreme elevation of the plasma concentration in an elderly non-small-cell lung cancer patient


1 Department of Internal Medicine, Division of Clinical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
2 Department of Clinical Pharmaceutical Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University Hospital, Japan

Date of Web Publication19-Apr-2012

Correspondence Address:
Yukari Tsubata
Clinical Fellow, Department of Internal Medicine, Division of Clinical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.95201

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 > Abstract 

We herein describe a case of drug-induced interstitial lung disease (ILD) following treatment with erlotinib. The plasma trough concentration of erlotinib at the time of the ILD diagnosis was extremely elevated compared with the plasma maximum concentration on day 1. We hypothesized that this phenomenon was associated with the pharmacodynamic interaction with a concomitant drug. The present case indicates that erlotinib-induced ILD was associated with a high plasma concentration of erlotinib. Oncologists should be aware of the possibility of ILD induced by erlotinib, especially for patients with co-morbidities.

Keywords: Elderly patient, epidermal growth factor receptor tyrosine kinase inhibitor, interstitial lung disease, non-small-cell lung cancer


How to cite this article:
Tsubata Y, Hamada A, Sutani A, Isobe T. Erlotinib-induced acute interstitial lung disease associated with extreme elevation of the plasma concentration in an elderly non-small-cell lung cancer patient. J Can Res Ther 2012;8:154-6

How to cite this URL:
Tsubata Y, Hamada A, Sutani A, Isobe T. Erlotinib-induced acute interstitial lung disease associated with extreme elevation of the plasma concentration in an elderly non-small-cell lung cancer patient. J Can Res Ther [serial online] 2012 [cited 2019 Dec 9];8:154-6. Available from: http://www.cancerjournal.net/text.asp?2012/8/1/154/95201


 > Introduction Top


Erlotinib is considered to be a promising new oral targeted therapeutic agent for metastatic non-small-cell lung cancer (NSCLC) after failure of at least one prior chemotherapy, and is associated with a favorable safety profile. [1],[2] The most common adverse events related to erlotinib treatment are skin rash and diarrhea, while the most serious adverse event reported was drug-induced interstitial lung disease (ILD). The incidence of ILD was less than 1% in the pivotal trials of erlotinib; nevertheless, ILD is usually a fatal complication. [2],[3] According to the post-marketing surveillance of gefitinib, another type of epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitor (TKI), the blood concentration was not correlated with the incidence of ILD. However, Hamada et al. suggested that the maximum plasma concentration (Cmax) of erlotinib on day 1 is one of the risk factors for ILD. [4]


 > Case Report Top


An 80-year-old male who had been detected to have lung nodules in his left lower lobe on radiological screening was admitted to our hospital in November 2008. A transbronchial lung biopsy revealed a diagnosis of NSCLC, histologically not specified, and his EGFR was not mutated. The clinical stage was considered T4N3M0; stage IIIB (UICC ver. 6.0). He had a heavily smoking habit (96 packs-year); however, he had quit 10 years prior. His past history also included hypertension, insomnia and irritable bowel syndrome. He had received continuous medical treatment for co-morbidities, such as a calcium blocker, magnesium oxide, polycarbophil calcium and brotizolam through the all treatment periods.

Soon after admission to the hospital, he received carboplatin (AUC 3) and paclitaxel (90 mg/m 2 ) bi-weekly chemotherapy. After four courses treatment, the patient was judged to have progressive disease (PD). We had selected monotherapy using docetaxel (60 mg/m 2 ) for the 2 nd line treatment. However, the patient developed grade 4 neutropenia on two occasions, and also revealed radiological evidence of PD while receiving docetaxel. Therefore, we selected oral erlotinib (150 mg daily) for the 3 rd line treatment, which was initiated in August 2009.

On day 2 of the erlotinib treatment, he complained of difficulty in swallowing, and therefore the administrations of powdered medicines including magnesium oxide and polycarbophil calcium were discontinued. On day 5, he complained of dyspnea, and his SpO 2 was 92%. The next day, a chest computed tomography (CT) revealed new bi-lateral diffuse ground-glass opacities [see [Figure 1]a, but there was no evidence of heart failure, pulmonary infarction or embolization. Furthermore, we examined electrocardiogram and echocardiography, blood testing and culture. There was no evidence of heart failure or infection. We diagnosed the patient with drug-induced ILD, and immediately withdrew erlotinib. The patient was started on intravenous methylprednisolone (1 mg/kg daily, then after 1 g bolus therapy for 3 days) and sivelestat sodium hydrate (4.8 mg/kg for two weeks) for the acute lung injury.
Figure 1: The chest CT image of the present case on day 6 after the diagnosis of ILD (a) and on day 16 after corticosteroid therapy (b). Although the chest CT revealed bilateral diffuse ground-glass opacities (GGO) and pleural effusion at the left lobe (a), the GGO had disappeared on day 16 (b)

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On day 16 after the start of erlotinib (on day 10 after the ILD diagnosis), his symptoms and chest CT findings improved [Figure 1]b. Although his general condition tended to stabilize gradually after starting steroid treatment, he suddenly developed convulsions on two weeks after being diagnosed with ILD. The patient's state of consciousness gradually deteriorated, and he died on day 27 (on day 21 after the ILD diagnosis). The cause of death was regarded as cerebral infarction with the progress of cancer.

For evaluation of his erlotinib pharmacokinetics, we obtained blood samples from patient on day 1 and on the day of diagnosis of ILD as the trough plasma concentration (Ctrough). Concentration of erlotinib in plasma was determined by a validated high-performance liquid chromatography method. [5] However, the plasma concentrations of erlotinib were very low level (0.49-0.85 μg/ml) on day 1, while we had recognized extreme elevation of the Ctrough (3.62 μg/ml) at the time of the ILD diagnosis [Figure 2].
Figure 2: The plasma concentration of erlotinib on day 1 and, the steady-state concentration (C trough) on day 6. Although the plasma concentration of erlotinib on day 1 was very low, the C trough (day 6) was extremely elevated

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 > Discussion Top


The present case indicates that erlotinib-induced ILD was associated with a high plasma concentration of the drug, which might have occurred due to pharmacodynamic drug interactions with one of his other therapeutic agents. Therefore, oncologists should be aware of the potential for ILD induced by erlotinib, especially for patients with co-morbidities.

Although the molecular mechanisms leading to ILD remain unknown, a multivariate analysis revealed that male gender, history of smoking, and the coexistence of interstitial pneumonia or pre-existence of pulmonary fibrosis, previous chemotherapy and a poor PS were all significant risk factors. [6],[7],[8],[9] The present case also had plural risk factors for ILD, such as male gender, a poor PS, history of smoking and previous chemotherapy. Hamada et al. suggested that there was a significant association between developing grade 2 or higher toxicity and the Cmax of erlotinib on day 1, and this might be one of the risk factors for ILD. [4] Phase I studies showed that the Css of erlotinib (150 mg/day orally) was 1.37-1.64 μg/ml, [10],[11] while the Ctrough of the present case on day 6 was 3.62 μg/ml. Particularly important, the Ctrough of erlotinib was extremely increased compared with the Cmax on day 1, and this phenomenon might have been associated with the ILD. Although there are many drugs that have possibility of causing ILD and the patient was on several concomitant medications, some of these drugs were stopped including magnesium oxide, on day 2. It has been suggested that alkalization of the gastric pH can cause a decrease in the absorption of erlotinib. Because magnesium oxide can increase the pH of gastric contents, we hypothesized that this effect could have influenced the erlotinib pharmacokinetics, possibly decreasing its absorption on day 1. Further investigation will be necessary to determine the pharmacokinetics of erlotinib when concomitant drugs that have potential of influence its absorption are used.

In conclusion, oncologists should recognize that kinase inhibitors such as erlotinib have the potential to cause acute interstitial pneumonia in some patients, especially those with co-morbidities. Further investigations to identify the mechanism (s) of drug-induced ILD associated with EGFR-TKIs are warranted.

 
 > References Top

1.Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, et al. TRIBUTE Investigator Group. TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;23:5892-9.  Back to cited text no. 1
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2.Shepherd FA, Rodringues PJ, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32.  Back to cited text no. 2
    
3.Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R. FDA drug approval summary: Erlotinib (Tarceva) tablets. Oncologist 2005;10:461-6.  Back to cited text no. 3
[PUBMED]  [FULLTEXT]  
4.Hamada A, Sasaki J, Saeki S, Iwamoto N, Inaba S, Ushijima S, et al. Association of pharmacokinetics and germ-line mutations in EGFR and ABC transporters with erlotinib toxicity in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 2009;27 Suppl:15s.  Back to cited text no. 4
    
5.Lepper ER, Swain SM, Tan AR, Figg WD, Sparreboom A. Liquid-chromatographic determination of erlotinib (OSI-774), an epidermal growth factor receptor tyrosine kinase inhibitor. J Chromatogr B Analyt Technol Biomed Life Sci 2003;796:181-8.  Back to cited text no. 5
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6.Inoue A, Saijo Y, Maemondo M, Gomi K, Tokue Y, Kimura Y, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003;361:137-9.  Back to cited text no. 6
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7.Makris D, Scherpereel A, Copin MC, Colin G, Brun L, Lafitte JJ, et al. Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer. BMC Cancer 2007;7:150-3.  Back to cited text no. 7
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8.Ando M, Okamoto I, Yamamoto N, Takeda K, Tamura K, Seto T, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2006;24:2549-56.  Back to cited text no. 8
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9.Takano T, Ohe Y, Kusumoto M, Tateishi U, Yamamoto S, Nokihara H, et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung Cancer 2004;45:93-104.  Back to cited text no. 9
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10.Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, 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;19:3267-79.  Back to cited text no. 10
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11.Yamamoto N, Horiike A, Fujisaka Y, Murakami H, Shimoyama T, Yamada 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;61:489-96.  Back to cited text no. 11
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    Figures

  [Figure 1], [Figure 2]


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