Cited by 144Lung Cancer Treatments and MutationsPharmacogenetics and Drug MetabolismSmoking Behavior and Cessation

Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers

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Hughes, Andrew N., O'Brien, Mary E.R., Petty, W. Jeffrey, Chick, Jonathan B., Rankin, Elaine, Woll, Penella J., Dunlop, David, Nicolson, Marianne +3 more·2009·Journal of Clinical Oncology

Abstract

PURPOSE: Cigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non-small-cell lung cancer (NSCLC) patients who smoke and compare the pharmacokinetics of erlotinib at the MTD in current smokers with 150 mg. PATIENTS AND METHODS: Cohorts of NSCLC patients currently smoking > or = 10 cigarettes per day for > or = 1 year received escalating doses of erlotinib for 14 days until dose-limiting toxicity (DLT). A separate cohort of patients was then randomly assigned to erlotinib at either MTD or 150 mg daily with pharmacokinetics assessed at day 14. Erlotinib was continued until progression or intolerable toxicity. RESULTS: Four dose levels were evaluated in 22 patients: 200, 250, 300, and 350 mg. DLT was observed in one of six patients at 300 mg (rash) and two of five patients at 350 mg (acneiform dermatitis and fatigue/decreased Eastern Cooperative Oncology Group performance status). Thirty-five patients were randomly assigned to 150 mg or 300 mg. Common adverse events (all grades) were: skin toxicity (150 mg, 29%; 300 mg, 67%), diarrhea (150 mg, 18%; 300 mg, 50%), and fatigue (150 mg, 12%; 300 mg, 17%). Erlotinib exposure was dose-proportional within dose range tested. Median steady-state trough erlotinib plasma concentrations were 0.375 and 1.22 microg/mL for 150 mg and 300 mg, respectively. CONCLUSION: The MTD of erlotinib in NSCLC patients who smoke was 300 mg. Steady-state trough plasma concentrations and incidence of rash and diarrhea in smokers at 300 mg were similar to those in former or never smokers receiving 150 mg in previous studies. The potential benefit of higher erlotinib doses in current smokers warrants further evaluation.

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Crossref · 10.1200/jco.2008.19.3995

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Authors
Hughes, A. N., O'Brien, M. E. R., Petty, W. J., Chick, J. B., Rankin, E., Woll, P. J., Dunlop, D., Nicolson, M., Boinpally, R., Wolf, J., & Price, A.
Affiliations
Aberdeen Royal Infirmary (GB)
Venue
Journal of Clinical Oncology
Published
2009-03-10
Volume
27
Issue
8
Pages
1220-1226
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
OpenAlex
W2140617449
Cited by
144
References
20
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 8 · 2018: 7 · 2017: 5 · 2016: 8 · 2015: 11 · 2014: 15 · 2013: 19 · 2012: 9
FWCI
15.44
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Oncology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
Keywords
erlotinib, cigarette smoking, non-small cell lung cancer, maximum tolerated dose, pharmacokinetics, dose-limiting toxicity, rash, diarrhea, dose escalation, drug metabolism
MeSH terms
Erlotinib Hydrochloride, Aged, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Quinazolines, Smoking, Cytochrome P-450 CYP1A1, Cytochrome P-450 CYP1A2, Maximum Tolerated Dose, Protein Kinase Inhibitors

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