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. 2017 Nov;83(11):2416-2425.
doi: 10.1111/bcp.13354. Epub 2017 Aug 17.

The Effects of Advanced Age and Serum α 1 -Acid Glycoprotein on Docetaxel Unbound Exposure and Dose-Limiting Toxicity in Cancer Patients

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Free PMC article

The Effects of Advanced Age and Serum α 1 -Acid Glycoprotein on Docetaxel Unbound Exposure and Dose-Limiting Toxicity in Cancer Patients

Hirotsugu Kenmotsu et al. Br J Clin Pharmacol. .
Free PMC article

Erratum in

  • Correction.
    Br J Clin Pharmacol. 2018 Oct;84(10):2449. doi: 10.1111/bcp.13694. Epub 2018 Jul 20. Br J Clin Pharmacol. 2018. PMID: 30216958 Free PMC article. No abstract available.

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.

Keywords: age; docetaxel; neutropenia; population pharmacokinetic analysis; unbound exposure; α1-acid glycoprotein.

Figures

Figure 1
Figure 1
Concentration–time profile of docetaxel in 51 patients. (○) patients aged <75 years, and (●) aged ≥75 years
Figure 2
Figure 2
Relationships between total body clearance of docetaxel and age (A), α1‐acid glycoprotein (AAG) level (B), and albumin (ALB) level (C)
Figure 3
Figure 3
Distribution of the unbound fraction of docetaxel (A) and correlations between the degree of unbound fraction and age (B), α1‐acid glycoprotein (AAG) (C) and albumin (ALB) (D). N.S., not statistically significant
Figure 4
Figure 4
Associations between percent decrease in absolute neutrophil count (ANC) at nadir and unbound exposure (fu·AUC) in patients aged <75 years (○) and patients aged ≥75 years (●) (A); Solid and dashed lines represent prediction by a sigmoid E max model in patients with baseline ANC ≤ 4341 μl−1 and > 4341 μl−1, respectively. Box plot of neutropenia grade vs. ANC at baseline (B); Box extending from the 25th to 75th percentile with the 50th percentile drawn inside the box and a line extending to the 95th percentile

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