Mass balance, excretion, and pharmacokinetics of a single oral dose of [14C]pixavir marboxil in healthy Chinese male participants

Background and Objective Cap-dependent endonuclease (CEN) inhibitors are a promising novel class of antiviral agents for influenza treatment. This phase I study aimed to evaluate the mass balance, excretion pathways, and pharmacokinetics of pixavir marboxil (TG-1000), a novel CEN inhibitor prodrug, in healthy humans. Methods Six healthy Chinese male participants received a single oral dose of 40 mg (100 μCi) [ 14 C]pixavir marboxil. Blood, urine, and fecal samples were collected at predefined intervals up to 384 h post-dose. Total radioactivity was determined using oxidative combustion and liquid scintillation counting. Pharmacokinetic parameters were calculated using non-compartmental analysis, and metabolite profiling was conducted using high-performance liquid chromatography coupled with radiochemical detection and high-resolution mass spectrometry. Results Intact pixavir marboxil was undetectable in plasma. Systemic exposure primarily consisted of its active metabolite, pixavir (TG-0527), and a subsequent glucuronide conjugate, TG-0600771. The geometric mean areas under the curve ( A U C 0 − ∞ ) for total radioactivity, pixavir, and TG-0600771 in six participants were 4,220 hng Eq./mL, 2,490 hng/mL, and 981 hng/mL, respectively. The administered radioactive dose demonstrated a mean cumulative recovery of 91.29%, with 85.62% recovered in feces and 5.68% in urine. Metabolite profiling identified pixavir and TG-0600771 as the major metabolites, with no major cytochrome P450 (CYP)-mediated oxidative metabolites observed in plasma. The single dose of [ 14 C]pixavir marboxil was safe and well-tolerated. Conclusion Pixavir marboxil exhibits a favorable pharmacokinetic profile characterized by rapid systemic conversion to its active metabolite, CYP-independent metabolism, and predominantly non-renal clearance. These favorable pharmacokinetic characteristics support a well-characterized disposition profile with limited reliance on CYP-mediated metabolism and renal excretion of active pixavir. Trial Registration This study was registered with Drug Clinical Trial Registration and Information Disclosure Platform, National Medical Products Administration (NMPA), number CTR20231822 ( http://www.chinadrugtrials.org.cn/ ).