Originally published as JCO Early Release 10.1200/JCO.2006.09.6115 on June 11 2007

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Cigarette Smoking and Irinotecan Treatment: Pharmacokinetic Interaction and Effects on Neutropenia

Jessica M. van der Bol, Ron H.J. Mathijssen, Walter J. Loos, Lena E. Friberg, Ron H.N. van Schaik, Maja J.A. de Jonge, André S.Th. Planting, Jaap Verweij, Alex Sparreboom, Floris A. de Jong

From the Department of Medical Oncology, Erasmus MC University Medical Center, Daniel den Hoed Cancer Center; Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; and the Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN

Address reprint requests to Floris A. de Jong, PhD, Erasmus MC University Medical Center, Daniel den Hoed Cancer Center, Department of Medical Oncology, Room AS-15, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; e-mail: f.a.dejong{at}erasmusmc.nl

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 · 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 · 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.

published online ahead of print at www.jco.org on June 11, 2007.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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  Neal L. Benowitz
  JCO 2007 25: 2646-2647 [Full Text]