title: Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature.
abstract: BACKGROUND
  Erlotinib is an agent in the class of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). This potentially fatal adverse reaction has been often described with gefitinib, but has been less well described for erlotinib. We here describe a case report of fatal interstitial lung disease in a Caucasian man associated with erlotinib and high erlotinib and metabolite plasma levels and discuss it in the context of all documented cases of erlotinib associated ILD.
  
  
  METHODS
  Our case was described and for the literature review a Pubmed and Google Scholar search was conducted for cases of erlotinib associated ILD. The retrieved publications were screened for relevant literature.
  
  
  RESULTS
  Besides our case, a total of 19 cases of erlotinib-associated ILD were found. Eleven out 19 cases had a fatal outcome and in only one case erlotinib plasma concentrations were measured and found to be high.
  
  
  CONCLUSIONS
  Erlotinib-associated ILD is a rare, serious and often fatal adverse reaction. Most likely, the cause for erlotinib-associated ILD is multifactorial and high drug levels may be present in patients without serious adverse reactions. However, considering the pharmacology of EGFR inhibitors, high drug and metabolite levels may play a role and future studies are warranted to identify risk factors and to investigate the role of elevated levels of erlotinib and its metabolites in the development of pulmonary toxicity.
authors.affiliation: Department of Pharmacy, Meander Medical Center, Utrechtseweg 160, 3818ES Amersfoort, The Netherlands. rob@terheine.nl
authors.forename: R
authors.initials: R
authors.lastname: ter Heine
authors.forename: R T A
authors.initials: RT
authors.lastname: van den Bosch
authors.forename: C M
authors.initials: CM
authors.lastname: Schaefer-Prokop
authors.forename: N A G
authors.initials: NA
authors.lastname: Lankheet
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: G H A
authors.initials: GH
authors.lastname: Staaks
authors.forename: M M
authors.initials: MM
authors.lastname: van der Westerlaken
authors.forename: M M
authors.initials: MM
authors.lastname: Malingré
authors.forename: J J G
authors.initials: JJ
authors.lastname: van den Brand
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D000069347:Erlotinib Hydrochloride; D017809:Fatal Outcome; D000077156:Gefitinib; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009203:Myocardial Infarction / Q000175:diagnosis; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects; D011799:Quinazolines / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib