Population pharmacokinetic and exposure-toxicity analyses of nab-paclitaxel after pegylated recombinant human granulocyte colony-stimulating factor administration in patients with metastatic breast cancer

Cancer Chemother Pharmacol. 2024 Oct;94(4):523-534. doi: 10.1007/s00280-024-04702-3. Epub 2024 Jul 31.

Abstract

Purpose: This study aimed to establish a population pharmacokinetic (PK) model to evaluate the dynamic relationship between the concentrations of total and unbound paclitaxel, and the exposure-response analysis of albumin-bound paclitaxel (nab-paclitaxel) after pegylated recombinant human granulocyte colony-stimulating factor (PEG-G-CSF) administration in patients with metastatic breast cancer.

Methods: A total of 653 concentrations corresponding to total paclitaxel and 334 concentrations corresponding to unbound paclitaxel were analyzed in 24 subjects who randomized received a single 260 mg/m2 dose of two nab-paclitaxel formulations with a 21-35-day washout period. PEG-G-CSF was administered to all the patients in each cycle to prevent neutropenia. The exposure-response relationships were evaluated using the exposure to total, albumin-coated, and unbound paclitaxel, as well as the reduction in neutrophil count. The exposure data were analyzed using nonlinear mixed-effect modeling. A linear regression model was used to test the statistical significance of the correlation between percentage of reduction in neutrophil count and exposure.

Results: The PK characteristics of total paclitaxel were described using a three-compartment model with first-order elimination, and a mechanism-based model incorporating linear release of nab-paclitaxel and the saturated binding of unbound paclitaxel to plasma components was established. The release ratio of paclitaxel from nab-paclitaxel was estimated to be 4.60% and the maximum unbound fraction (2.76%) was reached at the end of the infusion. The study found that a longer duration of total paclitaxel concentration > 0.19 µmol/L was significantly correlated with a reduction in neutrophil count (r2 = 0.23, P = 0.00062). Specifically, a duration of > 8.6 h was a predictor of a decreased neutrophil count.

Conclusion: The decrease in neutrophils induced by nab-paclitaxel was significantly correlated with the duration above a total paclitaxel concentration of 0.19 µmol/L despite the use of PEG-G-CSF.

Keywords: Nab-paclitaxel; Neutrophils; PEG-G-CSF; Pharmacokinetics/pharmacodynamics; Unbound paclitaxel.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Albumins* / administration & dosage
  • Albumins* / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / pathology
  • Female
  • Granulocyte Colony-Stimulating Factor* / administration & dosage
  • Granulocyte Colony-Stimulating Factor* / pharmacokinetics
  • Humans
  • Middle Aged
  • Models, Biological
  • Neoplasm Metastasis
  • Neutrophils / drug effects
  • Paclitaxel* / administration & dosage
  • Paclitaxel* / pharmacokinetics
  • Polyethylene Glycols* / administration & dosage
  • Polyethylene Glycols* / pharmacokinetics
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacokinetics

Substances

  • 130-nm albumin-bound paclitaxel
  • Paclitaxel
  • Albumins
  • Polyethylene Glycols
  • Granulocyte Colony-Stimulating Factor
  • pegylated granulocyte colony-stimulating factor, human
  • Recombinant Proteins
  • Antineoplastic Agents, Phytogenic