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
; 94(4): 523-534, 2024 Oct.
Article
in En
| MEDLINE
| ID: mdl-39080018
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Polyethylene Glycols
/
Breast Neoplasms
/
Granulocyte Colony-Stimulating Factor
/
Paclitaxel
/
Albumins
Limits:
Adult
/
Aged
/
Female
/
Humans
/
Middle aged
Language:
En
Journal:
Cancer Chemother Pharmacol
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Germany