Pharmacokinetics and tumor uptake of a derivatized form of paclitaxel associated to a cholesterol-rich nanoemulsion (LDE) in patients with gynecologic cancers

Objective: A cholesterol-rich nanoemulsion termed LDE concentrates in cancer tissues after injection into the bloodstream. The association of a derivatized paclitaxel to LDE showed lower toxicity and increased antitumoral activity as tested in a B16 melanoma murine model. Here, the pharmacokinetics of LDE–paclitaxel oleate and the ability of LDE to concentrate the drug in the tumor were investigated in patients with gynecologic cancers. Methods: Either LDE–paclitaxel oleate doubly labeled with [¹⁴C]-cholesteryl oleate and [³H]-paclitaxel oleate or [³H]-paclitaxel-cremophor was intravenously injected into eight patients. Blood samples were collected over 24 h to determine the plasma decay curves. Fractional clearance rate (FCR) and pharmacokinetic parameters were calculated by compartmental analysis. Also, specimens of tumors and the corresponding normal tissues were excised during the surgery for radioactivity measurement. Results: The LDE and paclitaxel oleate FCR were similar (0.092 ± 0.039 and 0.069 ± 0.027 h⁻¹, respectively, n = 5, P = 0.390). FCR of paclitaxel oleate associated to LDE was smaller than that of paclitaxel-cremophor (0.231 ± 0.128 h⁻¹, P = 0.028). Paclitaxel oleate T _1/2 and AUC were greater than those of paclitaxel-cremophor (T _1/2 = 14.51 ± 3.23 and 6.62 ± 2.05 h and AUC = 2.49 ± 0.35 and 1.26 ± 0.40, respectively, P = 0.009, P = 0.004). The amount of paclitaxel and LDE-radioactive labels in the tumor was 3.5 times greater than in the normal tissues. Conclusion: Paclitaxel oleate associated to LDE is stable in the bloodstream and has greater plasma half-life and AUC than those for paclitaxel-cremophor. LDE concentrates 3.5 times more paclitaxel in malignant tissues than in normal tissues. Therefore, association to LDE is an interesting strategy for using paclitaxel to treat gynecologic cancers.