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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2016

01-12-2016 | Original Article

Lack of effect of smoking status on axitinib pharmacokinetics in patients with non-small-cell lung cancer

Authors: May Garrett, Timothy Taylor, Diane R. Mould, Michael A. Amantea, Ying Chen, Antonella Ingrosso, Yazdi K. Pithavala

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2016

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Abstract

Purpose

Axitinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1–3, is approved for second-line treatment of advanced renal cell carcinoma. Axitinib is partially metabolized by cytochrome P450 1A2, which is induced by chronic heavy smoking. The effect of smoking on axitinib pharmacokinetics was evaluated in a non-small-cell lung cancer (NSCLC) patient population with a large number of active and ex-smokers.

Methods

Data were pooled from six clinical studies—serial pharmacokinetics from two healthy volunteer studies (n = 58) and sparse pharmacokinetics from four NSCLC studies (n = 152)—for a nonlinear mixed effects modeling (NONMEM v7.2) analysis. Demographics, smoking status, liver and renal function status, and Eastern Cooperative Oncology Group performance status were tested as covariates.

Results

There were 83 (40%) active smokers and 56 (27%) ex-smokers in the pooled dataset. Axitinib pharmacokinetics was adequately described with a linear, two-compartment model with a lagged first-order absorption. Final parameter estimates (inter-individual variability) were 16.1 L/h (59.1%) and 45.3 L (54.4%) for systemic clearance (CL) and central volume of distribution (Vc), respectively. Smoking status was found not to alter CL or Vc. Asian ethnicity and body weight were significant covariates for Vc, but were not considered clinically relevant since individual values of Vc for Asians were within the range of non-Asians.

Conclusions

Based on this analysis, smoking status does not affect area under plasma concentration–time curve, and thus no dose adjustment is required for smokers.
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Metadata
Title
Lack of effect of smoking status on axitinib pharmacokinetics in patients with non-small-cell lung cancer
Authors
May Garrett
Timothy Taylor
Diane R. Mould
Michael A. Amantea
Ying Chen
Antonella Ingrosso
Yazdi K. Pithavala
Publication date
01-12-2016
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-016-3164-x

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