Lack of effect of smoking status on axitinib pharmacokinetics in patients with non-small-cell lung cancer
| Autor: | May Garrett, Timothy J. Taylor, Michael Amantea, Diane R. Mould, Ying Chen, Yazdi K. Pithavala, Antonella Ingrosso |
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| Rok vydání: | 2016 |
| Předmět: |
Oncology
Adult Male Cancer Research medicine.medical_specialty Indazoles Lung Neoplasms Axitinib medicine.drug_class Metabolic Clearance Rate Renal function Toxicology 030226 pharmacology & pharmacy Models Biological Tyrosine-kinase inhibitor 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Renal cell carcinoma Internal medicine Carcinoma Non-Small-Cell Lung medicine Humans Pharmacology (medical) Lung cancer Protein Kinase Inhibitors Aged Pharmacology Volume of distribution Aged 80 and over business.industry Smoking Imidazoles Middle Aged medicine.disease NONMEM 030220 oncology & carcinogenesis Female business medicine.drug |
| Zdroj: | Cancer chemotherapy and pharmacology. 78(6) |
| ISSN: | 1432-0843 |
| Popis: | 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. 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. 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. Based on this analysis, smoking status does not affect area under plasma concentration–time curve, and thus no dose adjustment is required for smokers. |
| Databáze: | OpenAIRE |
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