A semi-mechanistic population pharmacokinetic model of conversion kinetics of nab-paclitaxel to its unbound form in Chinese patients with metastatic breast cancer

Background: 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. Method: 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 Monte Carlo simulation. Results: A three-compartment model with first-order elimination was selected to describe the PK of total paclitaxel. 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. Unbound paclitaxel fraction was expressed as a function of nab-paclitaxel concentration. 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. Conclusion: This is the first study to determine relationship between total and unbound nab-paclitaxel concentrations using a semi-mechanical population PK model. The model established in this study can be used to elucidate the dissociation process of nab-paclitaxel and provide a basis for studies investigating the relationship between unbound paclitaxel and toxicity as well as efficacy against metastatic breast cancer.