Expanding paclitaxel's therapeutic window: Investigating the pharmacokinetic, clinical formulation and mechanistic aspects of paclitaxel‑lipoate conjugate

Paclitaxel (PTX) is among the most widely used antimicrotubular chemotherapy agents available from natural sources. It has a wide range of antitumor effectiveness, particularly against breast, ovarian and lung malignancies. IDD-1040 is a novel anticancer chemical conjugate that combines lipoic acid with PTX and demonstrates an anticancer efficiency superior to that of PTX alone. The aim of the present study was to investigate the analytical, formulation and pharmacokinetic aspects of IDD-1040, shedding light on its pharmacological behavior and the possible mechanisms underlying its enhanced anticancer activity. IDD-1040 was administered to mice as an intravenous bolus, and the pharmacokinetic parameters were determined over the following 7 days. The results revealed a total clearance of 1.689 l/h.kg, volume of distribution of 1.93 l/kg, average half-life of 1.14 h and terminal half-life of 8.64 h. Notably, the area under the curve of IDD-1040 was >14-fold higher than that of PTX, suggesting slower metabolism and that prodrug itself may have antitumor activity. An <i>in vitro</i> tubulin polymerization assay revealed distinct tubulin-binding characteristics for IDD-1040 compared with PTX. Due to the poor water solubility of IDD-1040, a formulation development experiment was conducted. In total, 31 formulations were prepared that became transparent when diluted with water. In addition, some formulations achieved a relatively high drug content (12 mg/g) without the use of surfactants. Moreover, they included fewer excipients compared with the formulations diluted with water, suggesting a promising approach for drug formulation. In summary, IDD-1040 exhibited extended circulation, efficient tissue distribution and reduced metabolite formation <i>in vitro</i>, warranting further exploration of its mechanisms of action and therapeutic potential. Future studies are recommended to assess the stability, pharmacokinetics and pharmacodynamics of these refined IDD-1040 formulations to gauge their suitability for clinical application.