Abstract A189: Influence of smoking on the pharmacology of taxane therapy.

Abstract

Abstract Background: Smoking interacts with the metabolism of several anti-cancer drugs such as erlotinib and irinotecan. It may also affect the incidence and severity of side effects and the efficacy of chemotherapy. The main objective of this study was to examine the effects of smoking on the bone marrow toxicities and pharmacokinetics (PK) of the taxanes docetaxel and paclitaxel. Both taxanes are metabolized through a CYP3A-based conversion. Methods: 566 patients (429 non-smokers and 137 smokers) were treated with docetaxel or paclitaxel. We determined their toxicity profiles and PK parameters. PK samples were measured by HPLC or LC-MS/MS, and individual PK parameters were estimated from previously developed population PK models by non-linear mixed effects modeling in the software NONMEM. P-values were calculated by the Mann-Whitney U or 2 tests, while multivariate logistic regression analysis was used to adjust for covariates. Results: Smokers treated with docetaxel (43% vs 57% p = 0.03) or paclitaxel (11% vs 25% p = 0.02) showed less grade 3–4 leucopenia (white blood cell count (WBC) < 2.0×109/L) than non-smokers. These effects remained apparent in a multivariate analysis correcting for dose and co-medication (docetaxel: odds ratio (OR) = 0.56, 95% confidence interval 0.32–0.97, p = 0.04; and paclitaxel: OR = 0.3, 95% CI 0.13–0.83, p = 0.02). There was also significantly less grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5×109/L) in smokers than in non-smokers (OR = 0.46, 95% CI = 0.26–0.81, p = 0.007) in docetaxel treated patients. However, the incidence of neutropenic fever did not differ between smoking groups. Furthermore, the percentage decrease in WBC and ANC from baseline to nadir did not differ between smoking groups. The protective effect of smoking on bone marrow counts is probably attributable to smokers having higher baseline WBC (9.2 vs. 7.5 ×109/L; p < 0.0001) and ANC (6.7 vs. 5.1 ×109/L; p = 0.002) than non-smokers. Docetaxel and paclitaxel clearance did not differ between smokers and non-smokers (docetaxel: 39.1 vs. 39.4 L/h; p = 0.99; paclitaxel: 463 vs. 450 L/h; p = 0.77). Conclusion: This is the first large study on the effects of smoking on the treatment of docetaxel and paclitaxel. Smokers had lower incidence of leucopenia and neutropenia, possibly because smoking induces bone marrow growth. However, this did not affect the incidence of neutropenic fever. As no effect on PK was seen, the inductive effect of smoking on CYP3A suggested by previous studies might be substrate dependent or less apparent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A189.