The pharmacokinetics of PEGylated liposomal doxorubicin are not significantly affected by sex in rats or humans, but may be affected by immune dysfunction

Abstract

PEGylated liposomal doxorubicin (PLD, Caelyx®, Doxil®) has been suggested to show significant sex-based differences in plasma clearance, as well as high inter-individual variability that may be driven by monocyte counts in cancer patients. This study aimed to establish if these differences are similarly observed in rats, which exhibit similar liposome clearance mechanisms to humans, and to use this model to identify sources of inter-individual and sex-based pharmacokinetic variability. The plasma and lymphatic pharmacokinetics of PLD were evaluated in male and female rats by quantifying doxorubicin as well as the 3H-labelled liposome. In general, the pharmacokinetics of doxorubicin and the 3H-liposome did not differ significantly between male and female rats when corrected for body surface area. Female rats did, however, show significantly higher doxorubicin concentrations in lymph compared to male rats. With the exception of serum testosterone concentrations in males, none of the physiological parameters evaluated correlated with plasma clearance. Further, reanalysis of published human data that formerly reported sex-differences in PLD plasma clearance similarly revealed no significant differences in PLD plasma clearance between males and females with solid tumours, but increased plasma clearance in patients with Kaposi's sarcoma (generally HIV+/immunocompromised). These data suggest that with the exception of lymphatic exposure, there are unlikely to be significant sex effects in the pharmacokinetics of liposomes, but immune function may contribute to inter individual variability.