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The effects of advanced age and serum α(1)‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients
AIM: α(1)‐Acid glycoprotein (AAG), which is a major binding protein of docetaxel, is considered to be a determinant for docetaxel pharmacokinetics. However, there are no reports about the impact of serum AAG on pharmacokinetics and pharmacodynamics in elderly patients treated with docetaxel. The aim...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651322/ https://www.ncbi.nlm.nih.gov/pubmed/28640540 http://dx.doi.org/10.1111/bcp.13354 |
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author | Kenmotsu, Hirotsugu Imamura, Chiyo K. Ono, Akira Omori, Shota Nakashima, Kazuhisa Wakuda, Kazushige Taira, Tetsuhiko Naito, Tateaki Murakami, Haruyasu Takahashi, Toshiaki Tanigawara, Yusuke |
author_facet | Kenmotsu, Hirotsugu Imamura, Chiyo K. Ono, Akira Omori, Shota Nakashima, Kazuhisa Wakuda, Kazushige Taira, Tetsuhiko Naito, Tateaki Murakami, Haruyasu Takahashi, Toshiaki Tanigawara, Yusuke |
author_sort | Kenmotsu, Hirotsugu |
collection | PubMed |
description | AIM: α(1)‐Acid glycoprotein (AAG), which is a major binding protein of docetaxel, is considered to be a determinant for docetaxel pharmacokinetics. However, there are no reports about the impact of serum AAG on pharmacokinetics and pharmacodynamics in elderly patients treated with docetaxel. The aim of this prospective study was to elucidate the effects of advanced age and serum AAG on docetaxel unbound exposure and neutropenia, dose‐limiting toxicity, in cancer patients. METHODS: Docetaxel was administered at 60 mg m(−2) to 51 patients with non‐small cell lung cancer, 17 of whom were ≥75 years of age. Pharmacokinetics, unbound fraction (fu), neutropenia, serum protein levels of AAG and albumin, as well as baseline absolute neutrophil count (ANC) were assessed during the first course. Population pharmacokinetic and pharmacodynamic analyses were performed to evaluate the influence of clinically relevant factors on docetaxel pharmacokinetics and neutropenia. RESULTS: Clearance of docetaxel and degree of fu were significantly associated with serum AAG level, but not with age. Area under the concentration–time curve of unbound docetaxel (fu·AUC) was significantly higher in patients aged ≥75 years (0.389 μg·h ml(−1), 95% CI; 0.329–0.448 μg·h ml(−1)) compared with patients aged <75 years (0.310 μg·h ml(−1), 95% CI; 0.268–0.352 μg·h ml(−1)). Percent decrease in ANC at nadir related to fu·AUC, and was dependent on baseline ANC. CONCLUSION: Regardless of ageing, serum level of AAG determines docetaxel unbound exposure and related dose‐limiting toxicity. Serum AAG level and ANC at baseline appear to be predictive of neutropenia for patients of all ages following the administration of docetaxel. |
format | Online Article Text |
id | pubmed-5651322 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-56513222017-10-26 The effects of advanced age and serum α(1)‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients Kenmotsu, Hirotsugu Imamura, Chiyo K. Ono, Akira Omori, Shota Nakashima, Kazuhisa Wakuda, Kazushige Taira, Tetsuhiko Naito, Tateaki Murakami, Haruyasu Takahashi, Toshiaki Tanigawara, Yusuke Br J Clin Pharmacol Pharmacokinetics AIM: α(1)‐Acid glycoprotein (AAG), which is a major binding protein of docetaxel, is considered to be a determinant for docetaxel pharmacokinetics. However, there are no reports about the impact of serum AAG on pharmacokinetics and pharmacodynamics in elderly patients treated with docetaxel. The aim of this prospective study was to elucidate the effects of advanced age and serum AAG on docetaxel unbound exposure and neutropenia, dose‐limiting toxicity, in cancer patients. METHODS: Docetaxel was administered at 60 mg m(−2) to 51 patients with non‐small cell lung cancer, 17 of whom were ≥75 years of age. Pharmacokinetics, unbound fraction (fu), neutropenia, serum protein levels of AAG and albumin, as well as baseline absolute neutrophil count (ANC) were assessed during the first course. Population pharmacokinetic and pharmacodynamic analyses were performed to evaluate the influence of clinically relevant factors on docetaxel pharmacokinetics and neutropenia. RESULTS: Clearance of docetaxel and degree of fu were significantly associated with serum AAG level, but not with age. Area under the concentration–time curve of unbound docetaxel (fu·AUC) was significantly higher in patients aged ≥75 years (0.389 μg·h ml(−1), 95% CI; 0.329–0.448 μg·h ml(−1)) compared with patients aged <75 years (0.310 μg·h ml(−1), 95% CI; 0.268–0.352 μg·h ml(−1)). Percent decrease in ANC at nadir related to fu·AUC, and was dependent on baseline ANC. CONCLUSION: Regardless of ageing, serum level of AAG determines docetaxel unbound exposure and related dose‐limiting toxicity. Serum AAG level and ANC at baseline appear to be predictive of neutropenia for patients of all ages following the administration of docetaxel. John Wiley and Sons Inc. 2017-08-17 2017-11 /pmc/articles/PMC5651322/ /pubmed/28640540 http://dx.doi.org/10.1111/bcp.13354 Text en © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Pharmacokinetics Kenmotsu, Hirotsugu Imamura, Chiyo K. Ono, Akira Omori, Shota Nakashima, Kazuhisa Wakuda, Kazushige Taira, Tetsuhiko Naito, Tateaki Murakami, Haruyasu Takahashi, Toshiaki Tanigawara, Yusuke The effects of advanced age and serum α(1)‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients |
title | The effects of advanced age and serum α(1)‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients |
title_full | The effects of advanced age and serum α(1)‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients |
title_fullStr | The effects of advanced age and serum α(1)‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients |
title_full_unstemmed | The effects of advanced age and serum α(1)‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients |
title_short | The effects of advanced age and serum α(1)‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients |
title_sort | effects of advanced age and serum α(1)‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients |
topic | Pharmacokinetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651322/ https://www.ncbi.nlm.nih.gov/pubmed/28640540 http://dx.doi.org/10.1111/bcp.13354 |
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