Physiologically based pharmacokinetic model of docetaxel and interspecies scaling: comparison of simple injection with folate receptor-targeting amphiphilic copolymer-modified liposomes

Abstract

1. To compare the disposition of docetaxel (DTX) in male/female rats after intravenous administration of simple injection and folate-poly(PEG-cyanoacrylate-co-cholesteryl cyanoacrylate)-modified liposomes utilising a physiologically based pharmacokinetic (PBPK) modelling method, and extrapolate this model to mice and humans by taking into account the interspecies differences in physiological- and chemical-specific parameters.

2. Four structural models for single organs were evaluated, and the whole-body PBPK model included artery, vein, lung, brain, heart, spleen, liver, gastrointestinal tract, kidney, muscle and remainder compartment.

3. Rats following modified liposomes administration were characterised by significant decrease in the partition coefficients for brain, spleen, liver and remainder compartment. The blood-to-plasma partition coefficient also decreased significantly, while a marked rise of partition coefficients for lung, kidney and muscle was revealed. Partition coefficient for heart was approximately 1.3-fold higher in females than males, while the decrease of intestinal clearance was revealed in females compared to males. The final model successfully characterised the time course of DTX in rats, mice and humans.

4. This PBPK model is beneficial to the prediction of the effects of DTX in different species. It also represented a platform to encompass both formulation- and sex-related effects on DTX disposition and elimination in the future.

Keywords:

• Biodistribution
• docetaxel
• folate-poly (PEG-cyanoacrylate-co-cholesteryl cyanoacrylate)-modified liposomes
• interspecies scaling
• physiologically based pharmacokinetic modelling

Declaration of interest

The authors declare no conflicts of interest.

Supplementary material available online Supplementary Figure S1 and Supplementary Table S1