Pharmacokinetic and pharmacodynamic analysis of neutropenia following nab-paclitaxel administration in Japanese patients with metastatic solid cancer

Cancer Chemother Pharmacol. 2020 Oct;86(4):487-495. doi: 10.1007/s00280-020-04140-x. Epub 2020 Sep 15.

Abstract

Purpose: To develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for neutropenia following nab-paclitaxel administration and identify factors associated with drug disposition and changes in neutrophil counts in patients with solid cancer.

Methods: PK/PD analysis by nonlinear mixed effects approach was performed using the data from 27 patients who participated in phase I studies of nab-paclitaxel monotherapy conducted in Japan. The patients were treated with either weekly (80, 100, or 125 mg/m2) or every 3 weeks (200, 260, or 300 mg/m2). The observed paclitaxel concentrations in whole blood and neutrophil counts in the first cycle were used for PK/PD analysis. Covariate analysis was performed to identify factors affecting PK and the decrease in neutrophil counts.

Results: The developed 3-compartment, non-linear PK model described relationships of body surface area with total body clearance and volume of distribution for the peripheral compartment. Covariate factors affecting neutrophil counts were age and serum albumin level. Simulation based on the developed PK/PD model showed a substantial impact of age and serum albumin level on the time course of neutrophil counts after nab-paclitaxel administration. Advanced age was related to greater decrease in neutrophil counts, and serum albumin level, inversely related to change in neutrophil counts.

Conclusion: We have developed a novel PK/PD model for nab-paclitaxel in which age and serum albumin level were considered clinically important covariate factors. This model needs to be further validated using a larger patient population.

Keywords: Nab-paclitaxel; Neutropenia; Neutrophil count; Pharmacodynamics; Pharmacokinetics.

MeSH terms

  • Adult
  • Aged
  • Albumins / administration & dosage
  • Albumins / adverse effects*
  • Albumins / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / adverse effects*
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Clinical Trials, Phase I as Topic
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Japan / epidemiology
  • Leukocyte Count
  • Male
  • Middle Aged
  • Models, Biological*
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Neutropenia / blood
  • Neutropenia / chemically induced*
  • Neutropenia / diagnosis
  • Neutropenia / epidemiology
  • Neutrophils
  • Paclitaxel / administration & dosage
  • Paclitaxel / adverse effects*
  • Paclitaxel / pharmacokinetics
  • Risk Factors

Substances

  • 130-nm albumin-bound paclitaxel
  • Albumins
  • Antineoplastic Agents, Phytogenic
  • Paclitaxel