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Preclinical, Clinical, and Translational Sciences

(W0930-05-29) Pharmacokinetic Differences of Paclitaxel and Cyclopamine in Healthy and HCC Mice when Co-administered via Polymeric Micelle and Cremophor EL

Wednesday, November 12, 2025
9:30 AM - 10:30 AM CT
Purpose: Hepatocellular Carcinoma (HCC) is a highly aggressive and heterogenous liver malignancy lacking non-surgical treatments that improve patient quality of life and survival. Our study involved the pharmacokinetic (PK) analysis of two formulations of co-delivering Paclitaxel (PTX) and Cyclopamine (CPA), both compounds that have shown efficacy in HCC
in vitro and in vivo. 

Methods: One formulation, termed M-CPA/PTX, was developed using a polymeric micelle which contained 2.5 mg each of PTX and CPA, while another formulation, termed Cremophor EL, was developed using a mixture of Cremophor EL: EtOH: saline (1:1:8) within which contained 1 mg/mL of each drug. The PK was evaluated in healthy C57BL/6 mice and C57BL/6 mice injected via with Hep-1-6-luc cells to induce an orthotopic HCC model. The mice were divided into the following groups: healthy M-CPA/PTX (n = 3), healthy Cremophor El (n = 3), HCC M-CPA/PTX (n = 4), HCC Cremophor EL (n = 5).  For M-CPA/PTX, mice were dosed with 5 mg/kg PTX and 3.33 mg/kg CPA. For Cremophor EL, mice were dosed with 4.25 mg/kg PTX and 4.30 mg/kg CPA. All doses were delivered intravenously. From each group, blood was drawn at pre-specified time points up to 24 hours. Samples were analyzed using a validated LCMS/MS method with LLOQ of 0.50 ng/mL, following a liquid-liquid extraction with the volume ratio of 5:1 with ACN: H2O (1:1 v/v) to blood sample. PK analysis was performed using a 1 compartment model of Phoenix WinNonlin™ (version 8.5.2) to derive the PK parameters. One- and two-way ANOVA with Tukey post hoc test were used to compare data across dosing groups with p-value < 0.05 for significance. AUC and Cmax are presented normalized by dose.

Results: For PTX from M-CPA/PTX in HCC mice, there was a significant increase in CL (0.83 vs 0.53 L/h/kg) and Vd (2.08 vs 1.21 L/kg), resulting in a significant decrease in Cmax [497.1 vs 810.3 (ng/mL)/(mg/kg)] and AUC0-∞ [1,209.8 vs 1,901.6 (h*ng/mL)/(mg/kg)] in comparison to those from Cremophor EL formulation (Table 1). For PTX in healthy mice, there was no significant difference between the formulations (Table 2). For CPA from M-CPA/PTX in HCC mice, there was a significant increase in CL, (1.15 vs 0.8 L/h/kg) resulting in a significant decrease in AUC0-∞ [890.1 vs 1,265.8 (h*ng/mL)/(mg/kg)] in comparison to Cremophor EL. For CPA in healthy mice, there was no significant difference between the formulations. PK parameters for both groups are summarized in Tables 1 and 2. Next, we compared the difference between healthy and HCC mice of each formulation. For PTX from the M-CPA/PTX formulation, there was a significant increase in CL (0.83 vs 0.57 L/h/kg) and decrease in AUC0-∞ [1,209.8 vs 1,748.6 (h*ng/mL)/(mg/kg)] in HCC mice, and for CPA, HCC mice had a significant decrease in Cmax. [256.6 vs 674.7 (ng/mL)/(mg/kg)], as compared to those in the healthy mice. In the Cremophor EL formulation, however, there were no significant difference in the PK of neither PTX nor CPA.

Conclusion: The PK of PTX and CPA was characterized from both formulations in healthy and HCC mice, respectively. In healthy mice, there was no significant difference in the PK of either drug between the formulations. However, in HCC mice, the PK profiles differed for both drugs between the two formulations. M-CPA/PTX yielded decreased exposure due to increased CL for both PTX and CPA, compared to those from Cremophor EL. In addition, the disease state of HCC increased the CL of both PTX and CPA from M-CPA/PTX; however, the Cremophor EL formulation was unaffected.

Acknowledgements: Funding Support: Gillson Longenbaugh Foundation. NCI R01 grant and Supplemental grant (#CA257842)


Table 1: PK Parameter Comparison by Formulation in HCC Mice


Table 2: PK Parameter Comparison by Formulation in Healthy Mice