Cigarette smoking during irinotecan therapy: Effects on pharmacokinetics and neutropenia

2506 Background: Irinotecan is mainly metabolized by CYP3A-mediated oxidation to form inactive substances and by esterase- cleavage to form its active metabolite SN-38, which is further conjugated by UGT1A-isozymes. Variability in the pharmacokinetics of irinotecan is extensive and largely unexplained. Several constituents of cigarette smoke are known to interact with drug metabolizing enzymes, e.g. CYPs and UGTs, and potentially affect treatment outcome with substrate drugs. Here, we retrospectively explored the effects of cigarette smoking on the pharmacokinetics and adverse effects of irinotecan. Methods: A total of 190 patients (49 smokers and 141 non-smokers) were eligible and had received irinotecan as a 3-weekly 90-minute infusion. Individual pharmacokinetic parameters were obtained using NONMEM. Complete toxicity data were available in a subset of 134 patients receiving the registered dose of 350 mg/m2 irinotecan or its flat- fixed dose-equivalent of 600 mg. Results: In smokers, the dose-normalize...