Correlation between erlotinib pharmacokinetics, cutaneous toxicity and clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC)

Objectives: 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 6 beta-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] mu mol/l and 0.37 [2.90] mu mol/mol creat in serum and urinary samples, respectively; at T2 drug concentrations were significantly lower (2.02 [4.05] mu mol/l and 0.23[4.47] mu mol/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] mu mol/l, respectively, p = 0.004) and had longer progression-free and overall survival. An inverse correlation between erlotinib serum levels and urinary 6 beta-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. (C) 2013 Elsevier Ireland Ltd. All rights reserved.