Introduction: FF-10832 is a liposome suspension optimized by Fujifilm nanotechnology containing 0.5 mg/mL GEM, cholesterol, HSPC, N-MPEG-DSPE. FF-10832 is expected to improve GEM PK and have strong anti-tumor effects. The PK and anti-tumor effects of FF-10832 were studied in mice and human pancreatic cancer xenograft models.
Methods: Single-dose murine plasma PK of FF-10832 1 mg/kg was compared to GEM 240mg/kg. In vivo activity of GEM 240 mg/kg and FF-10832 1-5 mg/kg IV once weekly were compared in human pancreatic cancer murine xenograft models; 2 subcutaneous (Capan-1 [GEM-sensitive] and BxPC-3 [GEM-resistant]), and 1 orthotopic (SUIT-2) model. The active form of GEM (GEM triphosphate [dFdCTP]) inhibits DNA synthesis. dFdCTP tissue concentrations following FF-10832 4mg/kg and GEM 240mg/kg were compared in these models.
Results: An extended plasma t½ (10.6 vs. 2.9 hours), lower clearance, and smaller volume of distribution were observed with FF-10832 vs. GEM, which correlated with greater dose exposure achieved with FF-10832 compared to GEM (AUClast 186000 vs. 73000 hr·ng/mL). FF-10832 demonstrated increased in vivo activity in SUIT-2, Capan-1, and BxPC-3 models at significantly lower doses compared to GEM. In the Capan-1 and BxPC3 models, FF-10832 showed dose-dependent tumor growth suppression with FF-10832 4 mg/kg and 5 mg/kg superior to that of GEM (p<0.001), respectively. Following 11 weekly doses in the SUIT-2 model, the survival rate was 0% and 20% for vehicle and GEM 240 mg/kg vs. 13% and 60% for 2 and 4 mg/kg FF-10832, respectively. Median survival time was 60 (FF-10832 2 mg/kg) and 73 (GEM 240 mg/kg) vs. 26 days (vehicle) (p <0.001). Median survival was not reached at FF-10832 4 mg/kg. In all models, FF-10832 2 mg/kg (equivalent efficacy to GEM 240 mg/kg) showed no body weight gain suppression. The dFdCTP tumor/bone marrow AUC ratio was significantly higher following FF-10832 (dFdCTP AUC ratio = 7) compared with non-liposomal GEM (0.8).
Conclusions: FF-10832 is a stable liposomal GEM formulation demonstrating potent anti-tumor efficacy in solid tumor models with a favorable pharmacokinetic profile compared to non-liposomal GEM. Increased exposure achieved at lower GEM doses may potentially result in superior efficacy and a more tolerable safety profile for FF-10832 compared to non-liposomal GEM.
Citation Format: Takeshi Matsumoto, Tsukasa Kitahashi, Takashi Komori, Hiromu Kitahara, Kohei Ono, Naoki Yamada, Hiroyuki Iwamura, Kiyohito Takada, Shinji Hagiwara, Yasuhiro Shimada. Liposomal gemcitabine, FF-10832, improves gemcitabine (GEM) pharmacokinetics (PK) and increases anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5148. doi:10.1158/1538-7445.AM2017-5148