Human mass balance study of TAS-102 using ¹⁴C analyzed by accelerator mass spectrometry

Background: TAS-102 is an oral fluoropyrimidine prodrug composed of trifluridine (FTD) and tipiracil hydrochloride (TPI) in a 1:0.5 ratio. FTD is a thymidine analog, and it is degraded by thymidine phosphorylase (TP) to the inactive trifluoromethyluracil (FTY) metabolite. TPI inhibits degradation of FTD by TP, increasing systemic exposure to FTD. Methods: Patients with advanced solid tumors (6 M/2 F; median age 58 years; PS 0-1) were enrolled on this study. Patients in group A (N = 4) received 60 mg TAS-102 with 200 nCi [¹⁴C]-FTD, while patients in group B (N = 4) received 60 mg TAS-102 with 1000 nCi [¹⁴C]-TPI orally. Plasma, blood, urine, feces, and expired air (group A only) were collected up to 168 h and were analyzed for ¹⁴C by accelerator mass spectrometry and analytes by LC-MS/MS. Results: FTD: 59.8 % of the ¹⁴C dose was recovered: 54.8 % in urine mostly as FTY and FTD glucuronide isomers. The extractable radioactivity in the pooled plasma consisted of 52.7 % FTD and 33.2 % FTY. TPI: 76.8 % of the ¹⁴C dose was recovered: 27.0 % in urine mostly as TPI and 49.7 % in feces. The extractable radioactivity in the pooled plasma consisted of 53.1 % TPI and 30.9 % 6-HMU, the major metabolite of TPI. Conclusion: Absorbed ¹⁴C-FTD was metabolized and mostly excreted in urine. The majority of ¹⁴C-TPI was recovered in feces, and the majority of absorbed TPI was excreted in urine. The current data with the ongoing hepatic and renal dysfunction studies will provide an enhanced understanding of the TAS-102 elimination profile.