Marcello Tiseo1, Roberta Andreoli2, Francesco Gelsomino3, Paola Mozzoni2, Cinzia Azzoni4, Marco Bartolotti3, Beatrice Bortesi3, Matteo Goldoni2, Enrico Maria Silini4, Giuseppe De Palma5, Antonio Mutti6, Andrea Ardizzoni7. 1. Oncology Unit, University Hospital, Parma, Italy. Electronic address: mtiseo@ao.pr.it. 2. Department of Clinical and Experimental Medicine, University Hospital, Parma, Italy; INAIL Research Area, CERT, University of Parma, Parma, Italy. 3. Oncology Unit, University Hospital, Parma, Italy. 4. Section of Pathological Anatomy, University Hospital, Parma, Italy. 5. Department of Experimental and Applied Medicine, Section of Occupational Health and Industrial Hygiene, University of Brescia, Brescia, Italy. 6. Department of Clinical and Experimental Medicine, University Hospital, Parma, Italy. 7. Oncology Unit, University Hospital, Parma, Italy. Electronic address: aardizzoni@ao.pr.it.
Abstract
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 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.
OBJECTIVES: An association between skin toxicity and outcome has been reported for NSCLCpatients 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 NSCLCpatients. 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: Huixin Yu; Neeltje Steeghs; Cynthia M Nijenhuis; Jan H M Schellens; Jos H Beijnen; Alwin D R Huitema Journal: Clin Pharmacokinet Date: 2014-04 Impact factor: 6.447
Authors: Neeltje Steeghs; Alwin D R Huitema; Stefanie L Groenland; Remy B Verheijen; Markus Joerger; Ron H J Mathijssen; Alex Sparreboom; Jos H Beijnen; Jan H Beumer Journal: Clin Cancer Res Date: 2021-09-21 Impact factor: 12.531