A semi-mechanistic population pharmacokinetic model of conversion
kinetics of nab-paclitaxel to its unbound form in Chinese patients with
metastatic breast cancer
Information about the concentration of unbound paclitaxel over time
following administration of albumin-bound paclitaxel (nab-paclitaxel)
and its proportion to total paclitaxel in plasma remains unavailable.
The aim of this study was to establish a population pharmacokinetic (PK)
model to evaluate the dynamic relationship between total and unbound
concentrations of paclitaxel in Chinese patients with metastatic breast
cancer. A total of 653 concentrations corresponding to total and 334 to
unbound paclitaxel were analyzed in 24 subjects who received two cycles
of a single nab-paclitaxel dose of 260 mg/m2/cycle. The time course of
the fraction of unbound paclitaxel was analyzed by non-linear
mixed-effects modeling and Monte Carlo simulation. A mechanism-based
model incorporating linear dissociation of nab-paclitaxel and saturated
binding of free paclitaxel to plasma components was established to
describe the relationship between total and unbound paclitaxel.
Dissociation coefficient of nab-paclitaxel was estimated to be 4.60%,
while a maximum unbound fraction value of 2.76% was reached at the end
of infusion due to nonlinear binding kinetics of unbound paclitaxel.
This is the first study to determine relationship between total and
unbound nab-paclitaxel concentrations using a semi-mechanical population
PK model, revealing that unbound paclitaxel fraction was expressed as a
function of nab-paclitaxel concentration.