Absolute bioavailability of imidafenacin after oral administration to healthy subjects

What is already known about this subject • The absolute bioavailability of imidafenacin in rats and dogs is 5.6% and 36.1%, respectively. • The pharmacokinetic profiles of imidafenacin after oral administration have been revealed. • Imidafenacin is primarily metabolized to metabolites by CYP3A4 and UGT1A4. What this study adds • The absolute bioavailability of imidafenacin in human is 57.8%. • The pharmacokinetic profiles of imidafenacin after intravenous administration are revealed. • The formation of metabolites in the plasma is caused mainly by first-pass effects. Aims To investigate the absolute bioavailability of imidafenacin, a new muscarinic receptor antagonist, a single oral dose of 0.1 mg imidafenacin was compared with an intravenous (i.v.) infusion dose of 0.028 mg of the drug in healthy subjects. Methods Fourteen healthy male subjects, aged 21–45 years, received a single oral dose of 0.1 mg imidafenacin or an i.v. infusion dose of 0.028 mg imidafenacin over 15 min at two treatment sessions separated by a 1-week wash-out period. Plasma concentrations of imidafenacin and the major metabolites M-2 and imidafenacin-N-glucuronide (N-Glu) were determined. The urinary excretion of imidafenacin was also evaluated. Analytes in biological samples were measured by liquid chromatography tandem mass spectrometry. Results The absolute oral bioavailability of imidafenacin was 57.8% (95% confidence interval 54.1, 61.4) with a total clearance of 29.5 ± 6.3 l h−1. The steady-state volume of distribution was 122 ± 28 l, suggesting that imidafenacin distributes to tissues. Renal clearance after i.v. infusion was 3.44 ± 1.08 l h−1, demonstrating that renal clearance plays only a minor role in the elimination of imidafenacin. The ratio of AUCt of both M-2 and N-Glu to that of imidafenacin was reduced after i.v. infusion from that seen after oral administration, suggesting that M-2 and N-Glu in plasma after oral administration were generated primarily due to first-pass metabolism. No serious adverse events were reported during the study. Conclusions The absolute mean oral bioavailability of imidafenacin was determined to be 57.8%. Imidafenacin was well tolerated following both oral administration and i.v. infusion.