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


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).


CONCLUSIONS
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.
van der Bol
Jessica M
JM
Department of Medical Oncology, Erasmus MC University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Mathijssen
Ron H J
RH
Loos
Walter J
WJ
Friberg
Lena E
LE
van Schaik
Ron H N
RH
de Jonge
Maja J A
MJ
Planting
André S Th
AS
Verweij
Jaap
J
Sparreboom
Alex
A
de Jong
Floris A
FA
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004347:Drug Interactions; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000188:drug therapy*; D012907:Smoking / Q000009:adverse effects*; D017211:Treatment Failure; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme