The effects of advanced age and serum α1-acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients

Hirotsugu Kenmotsu, Chiyo Imamura, Akira Ono, Shota Omori, Kazuhisa Nakashima, Kazushige Wakuda, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami, Toshiaki Takahashi, Yusuke Tanigawara

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Aim: α1-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.

Original languageEnglish
Pages (from-to)2416-2425
Number of pages10
JournalBritish Journal of Clinical Pharmacology
Volume83
Issue number11
DOIs
Publication statusPublished - 2017 Nov 1

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docetaxel
Glycoproteins
Acids
Serum
Neoplasms
Neutropenia
Pharmacokinetics
Neutrophils

Keywords

  • age
  • docetaxel
  • neutropenia
  • population pharmacokinetic analysis
  • unbound exposure
  • α-acid glycoprotein

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

The effects of advanced age and serum α1-acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients. / Kenmotsu, Hirotsugu; Imamura, Chiyo; Ono, Akira; Omori, Shota; Nakashima, Kazuhisa; Wakuda, Kazushige; Taira, Tetsuhiko; Naito, Tateaki; Murakami, Haruyasu; Takahashi, Toshiaki; Tanigawara, Yusuke.

In: British Journal of Clinical Pharmacology, Vol. 83, No. 11, 01.11.2017, p. 2416-2425.

Research output: Contribution to journalArticle

Kenmotsu, H, Imamura, C, Ono, A, Omori, S, Nakashima, K, Wakuda, K, Taira, T, Naito, T, Murakami, H, Takahashi, T & Tanigawara, Y 2017, 'The effects of advanced age and serum α1-acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients', British Journal of Clinical Pharmacology, vol. 83, no. 11, pp. 2416-2425. https://doi.org/10.1111/bcp.13354
Kenmotsu, Hirotsugu ; Imamura, Chiyo ; 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 α1-acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients. In: British Journal of Clinical Pharmacology. 2017 ; Vol. 83, No. 11. pp. 2416-2425.
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abstract = "Aim: α1-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.",
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T1 - The effects of advanced age and serum α1-acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients

AU - Kenmotsu, Hirotsugu

AU - Imamura, Chiyo

AU - Ono, Akira

AU - Omori, Shota

AU - Nakashima, Kazuhisa

AU - Wakuda, Kazushige

AU - Taira, Tetsuhiko

AU - Naito, Tateaki

AU - Murakami, Haruyasu

AU - Takahashi, Toshiaki

AU - Tanigawara, Yusuke

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N2 - Aim: α1-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.

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KW - age

KW - docetaxel

KW - neutropenia

KW - population pharmacokinetic analysis

KW - unbound exposure

KW - α-acid glycoprotein

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