Effects of Smoking on the Pharmacokinetics of Erlotinib

Abstract

Purpose: To compare the pharmacokinetic variables of erlotinib in current smokers with nonsmokers after receiving a single oral 150 or 300 mg dose of erlotinib. Experimental Design: This was a single-center, open-label pharmacokinetic study in healthy male subjects. Subjects were enrolled into two treatment cohorts based on smoking status (current smokers and nonsmokers). The pharmacokinetic profile for erlotinib and its metabolite, OSI-420, was determined for each subject following each treatment. Results: Current smokers achieved significantly less erlotinib exposure following a single 150 or 300 mg dose than nonsmokers. Following the 150 mg dose, the geometric mean erlotinib AUC 0-1 in smokers was 2.8-fold lower than in nonsmokers and similar to that of nonsmokers at the 300 mg dose. C max in smokers was two-thirds of that in nonsmokers, and C 24h in smokers was 8.3-fold lower than in nonsmokers. The median C 24h of smokers at the 300 mg dose was slightly less than the C 24h of smokers at the 150 mg dose. The median C max was greater in smokers at the 300 mg dose than in nonsmokers at the 150 mg dose. Conclusion: This study confirms that the pharmacokinetics of erlotinib is different in current smokers and nonsmokers. The observation that AUC 0-1 and C 24h were significantly decreased in smokers compared with nonsmokers, and a smaller decrease in C max was observed, is consistent with increased metabolic clearance of erlotinib in current smokers.Although the recommendation to consider smoking status in clinical studies was made decades ago (1), the effect of smoking on pharmacokinetics has been studied for only a limited number of drugs (2 -5). Drugs for which patients' smoking status may have clinical significance include caffeine (6), chlordiazepoxide (7), chlorpromazine (8), diazepam (7), estradiol (9), flecainide (10, 11), haloperidol (12), heparin (13), imipramine (14), insulin (15), pentazocine (16), propoxyphene (7), propranolol (17), tacrine (4), and theophyline (18). Studies indicate that some of these drugs, including caffeine, imipramine, pentazocine, tacrine, and theophyline, are likely affected by induction of cytochrome P4501A enzymes.Erlotinib (TarcevaR, OSI Pharmaceuticals, Melville, NY; Roche, Basel, Switzerland; Genentech, South San Francisco, CA) is an orally active, potent selective inhibitor of the epidermal growth factor receptor tyrosine kinase (19). It is indicated for the treatment of patients with locally advanced or metastatic non -small cell lung cancer after failure of at least one prior chemotherapy regimen and in combination with gemcitabine for the treatment of patients with local advanced, unresectable, or metastatic pancreatic cancer. In the pivotal phase III non -small cell lung cancer trial, BR.21 (20), smoking history was the only factor with a significant and potentially clinically relevant interaction with treatment, indicating that erlotinib was more effective in never smokers than in current or former smokers. Further analyses have also shown that smoking hist...

Impact of Smoking Cessation on Global Gene Expression in the Bronchial Epithelium of Chronic Smokers

“…Seven of the eight validated genes overexpressed in current smokers-CYP1B1, four AKRs, ALDH3A1, and NQO1 (Table 2)-are involved in drug and/or carcinogen metabolism (9,10,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Polycyclic aromatic hydrocarbons in tobacco smoke are known to bind to and activate the aryl hydrocarbon receptor and thus induce CYP1B1 (10).…”

“…CYP1B1 expression is of special interest because it may contribute both to increased drug metabolism and to carcinogenesis of the aerodigestive tract (1,(18)(19)(20). The metabolic clearance of docetaxel, tamoxifen, gefitinib, erlotinib, and other cancer prevention and therapy drugs is enhanced by YP1B1 (9,(21)(22)(23). Upregulation of CYP1B1 and the six other validated overexpressed metabolizing genes by smoking is likely involved in the adverse interactions between smoking and drugs for lung cancer prevention and therapy; smoking cessation down-regulates these gene expressions and thus may reduce or eliminate the adverse drug interactions.…”

“…Three large randomized clinical trials to prevent lung cancer-the Alpha-Tocopherol, Beta-Carotene Prevention Study (5), Carotene and Retinol Efficacy Trial (6), and Lung Intergroup Trial (7)-showed that current heavy smokers had harmful interactions (higher lung cancer mortality, incidence, and recurrence) with preventive agents (versus control arms); agent effects in former smokers were generally neutral and were not readily interpretable in never smokers because of the exclusion or very limited number of these patients in these trials. Certain lung cancer therapy regimens have been shown to be less effective in current smokers than in former and never smokers (8,9). Smoking can stimulate the metabolic clearance of targeted anticancer therapies, undoubtedly diminishing therapeutic benefit (9,10).…”

“…Certain lung cancer therapy regimens have been shown to be less effective in current smokers than in former and never smokers (8,9). Smoking can stimulate the metabolic clearance of targeted anticancer therapies, undoubtedly diminishing therapeutic benefit (9,10). These data highlight the importance of understanding the biological effect of chronic smoking on lung tissue.…”

Overcoming CYP1A1/1A2 Mediated Induction of Metabolism by Escalating Erlotinib Dose in Current Smokers

“…8 The observation that former and never smokers experienced more adverse events (eg, rash and diarrhea) than current smokers suggests that variation in erlotinib exposure may also play a role. 4,10 Current smokers were found to have as much as a two-fold decrease in…”