title: Correlation between erlotinib pharmacokinetics, cutaneous toxicity and clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC).
abstract: OBJECTIVE
  An association between skin toxicity and outcome has been reported for NSCLC patients treated with erlotinib. Several explanations have been suggested, including pharmacokinetic and pharmacogenomic variability. The purposes of this study were to characterize erlotinib pharmacokinetic and to correlate drug serum and urine levels to toxicity and outcomes in advanced NSCLC patients.
  
  
  METHODS
  Patients with stage IV NSCLC consecutively treated with erlotinib in second- or third-line were enrolled. Biological samples (blood, urine and tumor specimens) were collected. Erlotinib levels in serum and urine samples of all patients after 7 (T1) and 30 (T2) days of treatment were quantified by LC-MS/MS analysis, along with urinary 6β-hydroxycortisol/cortisol ratio, as marker of metabolic phenotype of the CYP3A4/5 enzyme.
  
  
  RESULTS
  56 patients were recruited and for 46 all samples were available. At T1 erlotinib levels were 3.90 [2.13] μmol/l and 0.37 [2.90]μmol/mol creat in serum and urinary samples, respectively; at T2 drug concentrations were significantly lower (2.02 [4.05] μmol/l and 0.23 [4.47] μmol/mol creat, respectively). Patients with grade 3 skin toxicity showed serum T1 drug levels significantly higher than those with grade 0-2 (6.84 [2.28] vs. 3.08 [1.97] μmol/l, respectively, p=0.004) and had longer progression-free and overall survival. An inverse correlation between erlotinib serum levels and urinary 6β-hydroxycortisol/cortisol ratio was observed in patients with grade 3 skin toxicity.
  
  
  CONCLUSIONS
  These findings suggest that the pharmacokinetics and metabolism of erlotinib are related to skin toxicity and may support further studies where erlotinib dosing is tailored according to pharmacokinetic parameters.
authors.affiliation: Oncology Unit, University Hospital, Parma, Italy. Electronic address: mtiseo@ao.pr.it.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.affiliation: Department of Clinical and Experimental Medicine, University Hospital, Parma, Italy; INAIL Research Area, CERT, University of Parma, Parma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Andreoli
authors.affiliation: Oncology Unit, University Hospital, Parma, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gelsomino
authors.affiliation: Department of Clinical and Experimental Medicine, University Hospital, Parma, Italy; INAIL Research Area, CERT, University of Parma, Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Mozzoni
authors.affiliation: Section of Pathological Anatomy, University Hospital, Parma, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Azzoni
authors.affiliation: Oncology Unit, University Hospital, Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bartolotti
authors.affiliation: Oncology Unit, University Hospital, Parma, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bortesi
authors.affiliation: Department of Clinical and Experimental Medicine, University Hospital, Parma, Italy; INAIL Research Area, CERT, University of Parma, Parma, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Goldoni
authors.affiliation: Section of Pathological Anatomy, University Hospital, Parma, Italy.
authors.forename: Enrico Maria
authors.initials: EM
authors.lastname: Silini
authors.affiliation: Department of Experimental and Applied Medicine, Section of Occupational Health and Industrial Hygiene, University of Brescia, Brescia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Palma
authors.affiliation: Department of Clinical and Experimental Medicine, University Hospital, Parma, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mutti
authors.affiliation: Oncology Unit, University Hospital, Parma, Italy. Electronic address: aardizzoni@ao.pr.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
mesh_terms: D000368:Aged; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011799:Quinazolines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; C001380:6 beta-hydroxycortisol; D000069347:Erlotinib Hydrochloride; D006854:Hydrocortisone
keywords: Erlotinib; NSCLC; Pharmacokinetic; Skin toxicity