Plasma kinetics, uptake by neoplastic breast tissue and preliminary toxicity data of a cholesterol-rich microemulsion (LDE) associated to a paclitaxel (PCT) derivative

12038 Background: Previously we described the association of PCT to a cholesterol-rich microemulsion (LDE) that binds to low-density lipoprotein (LDL) receptors and concentrates in neoplastic tissues. The association is stable, preserves the anti-proliferative activity and reduces the toxicity to animals. The present study was designed to provide preliminary toxicity data on the LDE-PCT oleate formulation, to determine its plasma kinetics compared to that of commercial PCT and to verify the complex ability to concentrate in malignant breast tissue. Methods: To determine the plasma kinetics [3H]-PCT oleate associated to LDE labeled with [14C]-Cholesteryl oleate was intravenously injected into 3 pts and [3H]-commercial PCT into 2 pts 24 h before surgery. Blood samples were collected over the 24 h to quantified radioactivity and the pharmacokinetic parameters. Tumoral and normal breast tissue were excised during the surgery. Other 3 heavily pretreated pts with breast cancer were included in this study to assess toxicity. LDE-PCT (175 mg/m2) was administered as a 1-hour infusion at 3 week interval, without pre medication. Results: Fractional clearance rate (FCR) of LDE and of the drug were similar (0.030 ± 0.026 e 0.018 ± 0.018, respectively, P = 0.5742). The uptake of both [14C]-LDE and [3H]-paclitaxel oleate by breast malignant tissue was 2 and 3 fold greater than that of the normal breast tissue. The PCT oleate T1/2 (h) was greater than the commercial PCT (T½ = 18.97 ± 7.7 and 7.34 ± 0.40) and the clearence (L/h) of PCT oleate was lesser than the commercial (CL = 1.51 ± 0.18 and 7.95 ± 4.32). No hematological or neurotoxicity was found. Nausea and anorexia grade 1 was found only in one patient. Conclusion: Most of the drug is retained in the microemulsion until its removal from the circulation. The complex is stable and has greater plasma half life and lesser clearance than those for commercial one and can be concentrated in malignant breast tissue. Furthermore, LDE-PCT showed no considerable toxicity events in the 3 patients. Although data regarding response rates were not assessed, our preliminary results suggest that LDE-PCT may be a suitable and powerful weapon to treat breast cancer patients. No significant financial relationships to disclose.