Abstract 6886: Pharmacokinetics of paclitaxel and cyclopamine co-administered via polymeric micelle in HCC mice

Abstract Hepatocellular Carcinoma (HCC) is a highly aggressive form of liver cancer that is typically diagnosed at an advanced stage, leaving limited treatment options. The current non-surgical, first-line treatment, Sorafenib, is non-curative and does not improve patient quality of life. Our study involved pharmacokinetic (PK) analysis of Paclitaxel (PTX) and Cyclopamine (CPA) in an HCC mouse model. PTX is a microtubule-stabilizing drug, while CPA is a Hedgehog signaling pathway inhibitor. Together, the compounds arrest the cell cycle at the M and G phases, preventing tumor cell proliferation. The compounds were co-administered using a polymeric micelle formulation, termed M-CPA/PTX, which contained 2.5 mg each of PTX and CPA, with size of 70.63 ± 3.4 nm, PDI of 0.122 ± 0.038, and encapsulation efficiency of ≥80% for both compounds. The PK was evaluated in HCC transgenic mice expressing the C-MYC oncogene, after IV dosing of M-CPA/PTX at 5 mg/kg/drug every other day for 1, 2, and 3 doses, respectively. The injection volume ranged from 100 - 200 μL based on body weight. The mice were randomized into four groups: vehicle (n = 10), 1 dose (n =8), 2 doses (n=7), and 3 doses (n = 10). After the last dose of each group, PK blood samples were withdrawn at specified time points up to 24 hours when the tumor and organs were harvested. Samples were analyzed using a validated LCMS/MS method with an LLOQ of 0.5 ng/mL, following a liquid-liquid extraction with a volume ratio of 5:1 ACN: H2O (1:1 v/v) to blood sample or tissue homogenates. PK analysis was performed by both 1 and 2-compartment models using Phoenix WinNonlin™ to derive the PK parameters. ANOVA with the Tukey post hoc test was used to compare data across dosing groups with p-value <0.05 for significance. For PTX, the clearance (CL) was 43.17 ± 11.0 L/h/kg, not changing significantly after multiple dosing. The AUC had a notable, but insignificant, increase from 177.1 ± 44.23 h*ng/mL to 193.05 ± 31.76 h*ng/mL. The volume of distribution (Vd) was 91.3 ± 61 L/kg with no appreciable trend across the three groups. For CPA, the CL increased from 23.02 ± 10.34 L/h/kg to 63.48 ± 35.82 L/h/kg and 52.81 ± 31.45 L/h/kg after two and three doses, respectively. The AUC was 253.53 ± 103.2 h*ng/mL after one dose, which decreased to 230.55 ± 99.67 h*ng/mL and 153.96 ± 67.19 h*ng/mL after two and three doses, respectively. The Vd increased from 77.77 ± 12.91 L/kg to 130.57 ± 41.83 L/kg after three doses; however, this increase was not statistically significant. Tumor drug accumulation was also analyzed. In blood, the drug concentrations at 24 hr were below the LLOQ, so the absolute tumor concentration was evaluated. The concentrations were 9.24 ± 5.91 ng/g for PTX and 8.99 ± 4.1 ng/g for CPA. In conclusion, the PK of PTX and CPA in HCC mouse model from single and multiple dosing of M-CPA/PTX were characterized. Multiple dosing yielded no changes in CL and Vd of PTX, but increased CL and decreased AUC in CPA. Citation Format: Emanuel R. Baltrip, Lu Dai, Diana S-L Chow, Chun Li. Pharmacokinetics of paclitaxel and cyclopamine co-administered via polymeric micelle in HCC mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6886.