Abstract
Introduction: CLX-155 is a novel oral 5’-DFCR prodrug involving 5’-DFCR as an intermediate for generating 5-FU. Unlike capecitabine, CLX-155 undergoes esterase-mediated hydrolysis in the intestinal cells rather than the liver, leading to a different metabolic and pharmacokinetic profile. This study addresses the following research questions: 1) what is the single-dose PK of CLX-155, and 2) how does it compare to capecitabine?
Methods: This study was a parallel, single-dose study with four treatment groups. Investigators randomized 48 female Balb/C mice into four treatment groups: CLX-155 at 250 mg/kg and 500 mg/kg and capecitabine at 500 mg/kg and 1000 mg/kg. Animals received oral treatment once. Investigators evaluated PK parameters via noncompartmental analysis using WinNonlin Version 7.0 (Certara, Princeton, NJ).
Results: For CLX-155, the systemic exposure (Cmax and AUC0-t) of 5-FU, 5’-DFCR, and 5’-DFUR demonstrated proportionality to the administered dose. 5’-DFCR and 5’-DFUR showed a delayed Tmax compared to 5-FU. For capecitabine, the systemic exposure (Cmax and AUC0-t) of 5-FU, 5'-DFUR, and 5’-DFCR was less than dose proportional. CLX-155 demonstrated higher exposure at 500 mg/kg compared to capecitabine at the same dose. CLX-155 displayed marginally higher 5’-DFUR and 5-FU plasma AUC0-t in relation to capecitabine at equivalent 500 mg/kg doses. CLX-155 displayed marginally higher plasma AUC0-t of 5-FU and 5’-DFUR in relation to capecitabine at the equivalent doses of 500 mg/kg.
Conclusion: CLX-155 and capecitabine experience rapid absorption following oral administration and conversion to 5’-DFCR, 5’-DFUR, and 5-FU. The results suggest the conversion of CLX-155 to its metabolites 5’-DFUR and 5-FU was more efficient than that of capecitabine. Such observations have suggested that administration of CLX-155 at a lower dose level is a possibility. CLX-155’s infusion-like conversion to its metabolites 5’-DFUR and 5-FU provided a unique PK profile that may explain its antitumor activity in animals at half the dose of capecitabine reported in the previous study.