Influence of Smoking on the Pharmacokinetics and Toxicity Profiles of Taxane Therapy

Abstract

Purpose: Cigarette smoke is known to interact with the metabolism of several anticancer drugs. It may also affect the incidence and severity of adverse events and efficacy of chemotherapy. The main objective of this study was to examine the effects of smoking on the pharmacokinetics and toxicities of patients treated with docetaxel or paclitaxel.Experimental Design: Smoking status, toxicity profiles, and pharmacokinetic parameters (calculated by nonlinear mixed-effect modeling population analysis) were determined in 566 patients (429 nonsmokers and 137 smokers) treated with docetaxel or paclitaxel.Results: Smokers treated with docetaxel showed less grade IV neutropenia (35% vs. 52%; P ¼ 0.01) than nonsmokers. Smokers treated with paclitaxel had less grade III-IV leukopenia than nonsmokers (12% vs. 25%; P ¼ 0.03), and the white blood cell (WBC) nadir was lower in nonsmokers (median, 2.7 Â 10 9 /L; range, 0.05 Â 10 9 to 11.6 Â 10 9 /L) than in smokers (median, 3.3 Â 10 9 /L; range 0.8 Â 10 9 to 10.2 Â 10 9 /L; P ¼ 0.02). Of interest, significantly lower WBC counts and absolute neutrophil counts at baseline were seen in nonsmoking patients treated with paclitaxel (P ¼ 0.0001). Pharmacokinetic parameters were similar in smokers and nonsmokers for both taxanes.Conclusion: Cigarette smoking does not alter the pharmacokinetic determinants of docetaxel and paclitaxel. Smokers treated with docetaxel and paclitaxel have less neutropenia and leukopenia, but further research is warranted to elucidate this potential protective effect.

Cigarette Smoking and Gemcitabine-Induced Neutropenia in Advanced Solid Tumors

“…Therefore, the metabolic ‘phenotype’ involving the cytochrome P 450 enzymes may in fact be quite different in current and former smokers compared with nonsmokers. These findings support the hypothesis that cigarette smoking may accelerate chemotherapy metabolism and result in lower plasma concentrations of the chemotherapeutic agent, as demonstrated from multiple pharmacokinetic studies carried out in a number of drugs, including those previously mentioned [6–9, 13]. Reduced drug levels may lead to undertreatment in smokers, and, conversely, increased treatment-related neutropenia in non-smokers.…”

“…Similarly, smokers receiving irinotecan demonstrate increased clearance, lower area under the concentration curve, lower systemic exposure to the active drug metabolite, and less hematologic toxicity [8]. While the pharmacokinetics of taxanes were not altered with smoking, taxane-associated neutropenia was less pronounced in smokers versus nonsmokers [9]. Kanai et al [10] have similarly reported on an inverse relationship between gemcitabine and higher grades of neutropenia in Asian smokers treated for lung cancer.…”

Comparison of Abiraterone Acetate and Docetaxel with Androgen Deprivation Therapy in High-risk and Metastatic Hormone-naïve Prostate Cancer: A Systematic Review and Network Meta-analysis

“…Интерес-но, что несмотря на то, что курение не влияет на фар-макокинетику доцетаксела, была показана меньшая частота развития нейтропении IV степени у куриль-щиков (35 %) по сравнению с некурящими пациента-ми (52 %). Один из возможных механизмов этого эф-фекта заключается в повышении выработки КСФ ИЛ-6 и гранулоцитарными макрофагами [55].…”

Inter-patient variability in docetaxel pharmacokinetics: A review

“…Smoking has been studied as such and demonstrated to have no effect on docetaxel PK [85]. However, the incidence of grade 4 neutropenia was lower in smokers who were treated with docetaxel (35%) than in non-smokers (52%) [85].…”

“…Smoking has been studied as such and demonstrated to have no effect on docetaxel PK [85]. However, the incidence of grade 4 neutropenia was lower in smokers who were treated with docetaxel (35%) than in non-smokers (52%) [85]. One of the supposed mechanisms for this effect is that patients inhale small particles when smoking, which could result in IL-6 and granulocyte macrophage colony stimulating factor release, that encourages the proliferation of pre-cursors in the bone marrow [86][87][88].…”