Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia

Jessica Bol, HJ Mathijssen, Walter Loos, LE Friberg, Ron van Schaik, Maja de Jonge, AST Planting, Jaap Verweij, A Sparreboom, FA (Floris) de Jong*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

120 Citations (Scopus)

Abstract

PURPOSE: Several constituents of cigarette smoke are known to interact with drug metabolizing enzymes and potentially affect treatment outcome with substrate drugs. The purpose of this study was to determine the effects of cigarette smoking on the pharmacokinetics and adverse effects of irinotecan.

PATIENTS AND METHODS: A total of 190 patients (49 smokers, 141 nonsmokers) treated with irinotecan (90-minute intravenous administration on a 3-week schedule) were evaluated for pharmacokinetics. Complete toxicity data were available in a subset of 134 patients receiving 350 mg/m2 or 600 mg flat-fixed dose irinotecan.

RESULTS: In smokers, the dose-normalized area under the plasma concentration-time curve of irinotecan was significantly lower (median, 28.7 v 33.9 ng x h/mL/mg; P = .001) compared with nonsmokers. In addition, smokers showed an almost 40% lower exposure to SN-38 (median, 0.54 v 0.87 ng x h/mL/mg; P < .001) and a higher relative extent of glucuronidation of SN-38 into SN-38G (median, 6.6 v 4.5; P = .006). Smokers experienced considerably less hematologic toxicity. In particular, the incidence of grade 3 to 4 neutropenia was 6% in smokers versus 38% in nonsmokers (odds ratio [OR], 0.10; 95% CI, 0.02 to 0.43; P < .001). There was no significant difference in incidence of delayed-onset diarrhea (6% v 15%; OR, 0.34; 95% CI, 0.07 to 1.57; P = .149).

CONCLUSION: This study indicates that smoking significantly lowers both the exposure to irinotecan and treatment-induced neutropenia, indicating a potential risk of treatment failure. Although the underlying mechanism is not entirely clear, modulation of CYP3A and uridine diphosphate glucuronosyltransferase isoform 1A1 may be part of the explanation. The data suggest that additional investigation is warranted to determine whether smokers are at increased risk for treatment failure.

Original languageEnglish
Pages (from-to)2719-2726
Number of pages8
JournalJournal of Clinical Oncology
Volume25
Issue number19
DOIs
Publication statusPublished - 1 Jul 2007

Research programs

  • EMC MM-03-86-08
  • EMC OR-01-25-01

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