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Originally published as JCO Early Release 10.1200/JCO.2006.09.6115 on June 11 2007 © 2007 American Society of Clinical Oncology. Cigarette Smoking and Irinotecan Treatment: Pharmacokinetic Interaction and Effects on Neutropenia
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.
Tobacco is the single largest preventable cause of cancer in the modern world.1 It accounts for approximately 30% of all cancer deaths. In addition to the fact that it explains almost 90% of lung cancer deaths, it is linked to more than 10 different cancer types, including cancer of the head and neck, esophagus, bladder, pancreas, cervix, kidney, stomach, colon, and rectum, and some leukemias, as well as to an earlier onset of cancer and to a worse prognosis.2-4 Despite all antismoking campaigns, there are currently about 1.3 billion smokers worldwide and this number is still increasing.5 Interestingly, little data are available on the prevalence of smoking in cancer patients. At the M.D. Anderson Cancer Center (Houston, TX), smoking rates of 30% among both male and female cancer patients were reported.6 In addition, 25% of patients referred to the Canadian Ottawa Regional Cancer Center were smoking.7 These numbers are in concordance with smoking prevalence in the general population in the Americas, with estimates of 24% to 32% among men and 18% to 21% among women, respectively.5,8 Cigarette smoke contains several constituents known to interact with drug-metabolizing enzymes. For example, polycyclic aromatic hydrocarbons (PAHs) induce CYP1A1 and CYP1A2,9 both of which are isoforms of the cytochrome P-450 family (CYP) that is involved in the metabolism of almost all anticancer drugs,10 thereby interfering with the pharmacokinetic profile of drugs metabolized by these CYPs. For instance, the oral clearance of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, was shown to be 24% faster in smokers compared with nonsmokers,11 and this may affect overall survival in non–small-cell lung cancer.12 PAHs are also known to induce some isoforms of the uridine diphosphate glucuronosyltransferase (UGT) family,9 which includes important enzymes involved in glucuronic acid conjugation. For example, increased rates of glucuronidation of propranolol and codeine have been reported in smokers.13,14 In addition to PAHs, other cigarette constituents such as nicotine, carbon monoxide, and cadmium may also be involved in the modulation of the expression and function of enzymes and drug transporters involved in drug elimination.15,16 Against this background, the purpose of this study was to explore the effect of smoking behavior on the pharmacokinetics and adverse effects of irinotecan (Campto; Pfizer, Capelle aan den IJssel, the Netherlands), a topoisomerase-I inhibitor registered for the first- and second-line treatment of metastasized and/or inoperable colorectal cancer, which is known to be a substrate for several cytochrome P-450 and UGT1A isozymes (Fig 1) and drug transporters, in a large cohort of cancer patients.
Patients A total of 202 patients, previously enrolled in nine different prospective clinical trials with irinotecan between 1996 and 2005 that involved pharmacokinetic analyses,17-25 were included in this study. The common inclusion criteria were a histologically or cytologically confirmed diagnosis of any form of cancer that was believed to be sensitive to irinotecan or for which no other treatment options were available; age older than 18 years; Eastern Cooperative Oncology Group/WHO performance score less than 2; and adequate hematopoietic, hepatic, and renal functions. A specific exclusion criterion for the current analysis was the use of known CYP3A or UGT1A inducers or inhibitors. All trials were conducted according to the revised Declaration of Helsinki and were approved by the local medical ethical committee. Written informed consent was obtained from all patients.
Treatment
Smoking Status
Pharmacokinetic Analysis Relative extent of conversion of irinotecan into SN-38 (percentage), calculated as the molar AUC0 to 100 hours ratio of SN-38 to irinotecan x 100%, and the relative extent of glucuronidation of SN-38 into SN-38G, defined as the molar AUC0 to 100 hours ratio of SN-38G to SN-38, were considered as well. Although these measures reflect carboxylesterase capacity and UGT1A capacity, respectively, both measures are actually surrogate measures.31 Other factors, although less pronounced, may affect the measures as well, such as CYP3A-mediated inactivation and adenosine triphosphate binding cassette (ABC) drug transporter–mediated excretion.
UGT1A1*28 Genotyping
CYP3A Phenotyping
Pharmacodynamic Analysis
Statistical Analysis
Patients A total of 190 patients (49 smokers and 141 nonsmokers; Table 1) were assessable for analysis of the influence of smoking on the pharmacokinetic parameters of irinotecan. For 10 patients, smoking status could not be obtained with certainty. Two patients reported having quit smoking within 4 weeks before treatment and therefore were considered not eligible. Other former smokers quit smoking at least 2 months before their first irinotecan treatment and were thus considered as nonsmokers. Except for age and bilirubin, none of the baseline demographic data, including UGT1A1*28 genotype status, were significantly different between smokers and nonsmokers (Table 1).
Smoking and Irinotecan Pharmacokinetics Smokers showed about an 18% faster clearance of irinotecan than nonsmokers (median, 34.8 v 29.5 L/h; P = .001; Table 2). The systemic exposure to the active metabolite SN-38 was almost 40% lower in smokers (median dose-normalized AUC0 to 100 hours, 0.54 v 0.87 ng · h/mL/mg; P < .001), whereas no significant effect on the glucuronide conjugate of SN-38 (ie, SN-38G) was observed (Table 2). Mean dose-normalized plasma concentration versus time profiles of both irinotecan and SN-38 for smokers and nonsmokers are shown in Figure 2. In addition, the relative extent of conversion of irinotecan into SN-38, and in particular, the relative extent of glucuronidation of SN-38 into SN-38G, were significantly different between both groups; the relative extent of conversion was lower (median, 2.9% v 3.8%; P < .001) and the relative extent of glucuronidation was higher in smokers (median, 6.6 v 4.5; P = .006; Table 2). No dose-effect relationship could be established between the pharmacokinetic parameters and the amount of smoked cigarettes (data not shown).
In the subgroup of patients not carrying a single UGT1A1*28 allele (ie, TA6/TA6 patients), results were comparable. In particular, systemic exposure to SN-38 was significantly lower in smokers (n = 21) compared with nonsmokers (n = 43; median dose-normalized AUC0 to 100 hours, 0.54 v 0.82 ng · h/mL/mg; P < .001). Likewise, the relative extent of glucuronidation was higher in smokers (median, 6.75 v 4.41; P = .006).
Smoking and CYP3A Phenotype
Smoking and Irinotecan-Related Toxicity In the subgroup of patients treated with the registered dose of irinotecan (350 mg/m2 or a 600-mg flat-fixed dose), smokers (n = 35) experienced significantly less hematologic toxicity than nonsmokers (n = 99). Specifically, the median WBC values decreased to 5.3 x 109/L in smokers and 3.0 x 109/L in nonsmokers (P < .001), whereas the respective ANC nadir values were 3.3 x 109/L versus 1.6 x 109/L (P < .001). Incidences of grade 3 to 4 leucopenia (9% v 32%; OR, 0.20; 95% CI, 0.06 to 0.69; P = .006) and neutropenia (6% v 38%; OR, 0.10; 95% CI, 0.02 to 0.43; P < .001) were significantly lower in smokers compared with nonsmokers (Table 4). The AUC0 to 100 hours of both irinotecan and SN-38 were correlated with both the nadir of WBC (  = –0.434 and = –0.582, respectively; P < .001) and the nadir of ANC ( = –0.394 and = –0.593, respectively; P < .001). Although the incidence of grade 3 to 4 diarrhea was 60% lower in smokers, no significant difference between smokers and nonsmokers was found (6% v 15%; OR, 0.34; 95% CI, 0.07 to 1.57; P = .149).
This study suggests that smoking significantly affects the pharmacokinetics and toxicity profile of irinotecan. The clearance of irinotecan was significantly faster in smokers. In addition, smokers showed a more extensive glucuronidation of SN-38, resulting in reduced systemic exposure to the active metabolite SN-38, which likely contributed to less severe hematologic toxicity. The data complement previous knowledge on the clinical pharmacology of irinotecan, and may have important practical implications for its optimal use. The incentive for this study was the recent finding that smoking might affect the partitioning of irinotecan in RBCs in vitro.35 In addition, because irinotecan is subject to a highly complex metabolic pathway, involving several phase I and II enzymes and drug transporters (Fig 1), an effect of individual constituents of cigarette smoke on these metabolic pathways was hypothesized. The decreased exposure to irinotecan in smokers observed in this study may be explained by induction of CYPs. Although irinotecan is not metabolized by CYPs typically associated with drug interactions caused by smoking, such as CYP1A1 and CYP1A2,36,37 it is known to be highly sensitive to CYP3A induction.21 Previous studies have suggested that smoking may induce CYP3A. For example, the systemic exposure to quinine, a known CYP3A substrate, was found to be 44% lower in smokers compared with nonsmokers.38,39 In addition, in two in vitro studies, nicotine, the addictive constituent of cigarettes, caused induction of CYP3A transcription by activating the nuclear receptor NR1I2 (pregnane X receptor).40,41 The possibility of CYP3A modulation by cigarette smoking is supported by the current finding that measures of exposure to the CYP3A probe drugs midazolam and erythromycin were lower in smokers, although this did not reach statistical significance, presumably due to the small sample size studied. It is notable that reduced systemic exposure in smokers has also been reported for the CYP3A4 phenotyping probe alprazolam.42 However, other studies involving CYP3A substrates have not confirmed this influence of smoking,43-46 suggesting that, if CYP3A is the causative regulator, this effect might be dependent on the substrate drug. Alternatively, modulation of carboxylesterases could explain the effects on irinotecan clearance and the relative extent of conversion of irinotecan into SN-38. Indeed, the relative extent of conversion is lower in smokers, at first suggesting inhibition of carboxylesterases and less effective conversion of irinotecan into SN-38. However, conflicting with this hypothesis, smokers were found to have lower systemic concentrations of irinotecan. Apart from CYP3A modulation, this latter finding might be explained by induction of functional expression of carboxylesterases. In this case, the apparent lower extent of conversion of irinotecan into SN-38 should be attributed to a higher glucuronidation of SN-38 into SN-38G, compensating for the metabolism of additionally formed SN-38. Indeed, there is some in vitro research supporting the hypothesis that carboxylesterases might be modulated by certain PAHs found in cigarette smoke.47 However, to date, there are insufficient data to draw any conclusions regarding the influence of smoking on carboxylesterase activity in relation to irinotecan therapy. In addition to CYPs and carboxylesterases, cigarette smoke is also known to induce glucuronidation of certain drugs.48,49 Furthermore, there is evidence that cigarette constituents can specifically induce UGT1A.50,51 The higher relative extent of glucuronidation of SN-38 into SN-38G observed in smokers can be explained by induction of UGT1A1. To excrete the breakdown products of hemoglobin, bilirubin is glucuronidized by UGT1A1. In line with earlier published data,52-63 somewhat lower baseline bilirubin concentrations in smokers were found in the current study (median, 7.0 v 9.0 µmol/L; P < .001), indicating that smoking cigarettes may induce UGT1A1. This theory has also been proposed by others,64 although the lower bilirubin concentration in smokers might also be explained by an effect on specific drug transporters, such ABCC2 (as canalicular multispecific organic anion transporter) and the organic anion transporting polypeptide 8. Given that the distribution of UGT1A1*28, which is known to be related to both bilirubin levels and clearance of SN-38, did not differ between smokers and nonsmokers, it is unlikely that the different bilirubin levels can be attributed to differences in UGT1A1*28 status. The lower exposure to SN-38 in smokers is in line with the lower bilirubin level in this group of patients and strongly suggests that cigarette smoke induces UGT1A1, indirectly lowering the risk of severe adverse effects and the chance of therapeutic benefit as a consequence of the lower SN-38 exposure. Indeed, in this study, smokers had remarkably less hematologic toxicity. Although smokers are known to have higher WBC counts,65-67 in this particular population the baseline WBC counts in smokers were only marginally higher (P = .077 and P = .176 for WBC and ANC, respectively; Table 1), suggesting that the higher nadirs and the smaller percentage decrease at nadir seen in smokers during irinotecan therapy cannot be attributed solely to the direct effects of their smoking habit on bone marrow function. Whether the therapeutic outcome was affected could not be investigated reliably in the present study because of the design of the conducted trials and the heterogeneity of the included patients. Induction of other UGT1A enzymes known to be capable of SN-38 glucuronidation, such as UGT1A7 and UGT1A9,68,69 should not be disregarded. Whether the higher glucuronidation capacity in smokers is to be attributed to induction of UGT1A isoforms expressed in the liver or extrahepatically remains to be investigated. For example, Villard et al49 found that mice exposed to cigarette smoke had enhanced glucuronidation capacity in the liver and particularly in the lung. In addition to these effects on phase I and II enzymes, induction of ABC transporters by smoking can result in faster elimination of irinotecan and its metabolites, and hence in decreased exposure.68 In rats, increased expression of placental ABCB1 (P-glycoprotein) was observed after tobacco exposure,70 indicating that cigarette smoke may influence irinotecan pharmacokinetics via modulation of ABC transporters. Furthermore, immunohistochemical analysis of non–small-cell lung carcinomas in 94 patients revealed higher ABCB1 expression in smokers (58% v 9%; P < .001).71 However, no difference in placental expression of ABCB1 and ABCG2 (breast cancer resistance protein) was seen between smoking and nonsmoking mothers.72 In addition, no effect of nicotine metabolites on organic anion transport by ABCC2 (canalicular multispecific organic anion transporter) was found in vitro.73 In summary, at present, there are insufficient data to make conclusions regarding the influence of smoking on ABC transporters. Although additional investigation is required to determine the underlying mechanism of the current observations, they may have important clinical implications. Smoking before and during irinotecan treatment seems to have unfavorable effects. The data presented suggest that knowledge of smoking behavior before irinotecan treatment needs to be taken into consideration. Given that our analysis was conducted retrospectively in a heterogeneous patient population, recommendations regarding dose adjustments for smokers or smoking cessation during irinotecan treatment cannot be made at present. In addition, no data are available about the effect of smoking on outcome of irinotecan treatment. Furthermore, influence of smoking also should be investigated in the frequently used combination schemes with irinotecan. In conclusion, this study suggests that smoking is associated with reduced systemic exposure to irinotecan and its active metabolite SN-38, and subsequently, less severe hematologic toxicity. Given that they both more or less depend on systemic irinotecan and SN-38 exposure, less hematologic toxicity indirectly may reflect a less favorable therapeutic outcome. Therefore, it should be stressed that the lower incidence and severity of hematologic toxicity of irinotecan therapy in smoking patients is likely an unbalanced and unwanted adverse effect. Although the underlying actual mechanism is not completely clear, the effects on irinotecan pharmacokinetics probably can be ascribed to modulation of enzymes involved in the metabolism of irinotecan, in particular CYP3A and UGT1A1. Although results presented in this article indicate that therapeutic outcome of irinotecan might be affected negatively by smoking, whether smokers should quit smoking or should receive a higher dose (if smoking cessation is not an option) to achieve equal outcome to irinotecan treatment as nonsmokers remains to be investigated.
The author(s) indicated no potential conflicts of interest.
Conception and design: Floris A. de Jong Provision of study materials or patients: Ron H.J. Mathijssen, Maja J.A. de Jonge, André S.Th. Planting, Jaap Verweij, Floris A. de Jong Collection and assembly of data: Jessica M. van der Bol, Ron H.J. Mathijssen, Walter J. Loos, Lena E. Friberg, Ron H.N. van Schaik, Alex Sparreboom, Floris A. de Jong Data analysis and interpretation: Jessica M. van der Bol, Floris A. de Jong Manuscript writing: Jessica M. van der Bol, Alex Sparreboom, Floris A. de Jong Final approval of manuscript: 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
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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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to calculate a corresponding P value. Based on a Bonferroni correction for five variables,
