The effects of advanced age and serum α 1 -acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients

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

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.

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Area Under Curve
  • Carcinoma, Non-Small-Cell Lung / blood
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Chemotherapy-Induced Febrile Neutropenia / blood
  • Chemotherapy-Induced Febrile Neutropenia / epidemiology
  • Chemotherapy-Induced Febrile Neutropenia / etiology
  • Docetaxel
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Lung Neoplasms / blood
  • Lung Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Orosomucoid / analysis*
  • Prospective Studies
  • Taxoids / pharmacology*
  • Taxoids / therapeutic use

Substances

  • Antineoplastic Agents, Phytogenic
  • Orosomucoid
  • Taxoids
  • Docetaxel