Abstract
1. The metabolism, pharmacokinetics, excretion and tissue distribution of a hepatitis C NS3/NS4 protease inhibitor, faldaprevir, were studied in rats following a single 2 mg/kg intravenous or 10 mg/kg oral administration of [14C]-faldaprevir.
2. Following intravenous dosing, the terminal elimination t1/2 of plasma radioactivity was 1.75 h (males) and 1.74 h (females). Corresponding AUC0–∞, CL and Vss were 1920 and 1900 ngEq · h/mL, 18.3 and 17.7 mL/min/kg and 2.32 and 2.12 mL/kg for males and females, respectively.
3. After oral dosing, t1/2 and AUC0–∞ for plasma radioactivity were 1.67 and 1.77 h and 11 300 and 17 900 ngEq · h/mL for males and females, respectively.
4. In intact rats, ≥90.17% dose was recovered in feces and only ≤1.08% dose was recovered in urine for both iv and oral doses. In bile cannulated rats, 54.95, 34.32 and 0.27% dose was recovered in feces, bile and urine, respectively.
5. Glucuronidation plays a major role in the metabolism of faldaprevir with minimal Phase I metabolism.
6. Radioactivity was rapidly distributed into tissues after the oral dose with peak concentrations of radioactivity in most tissues at 6 h post-dose. The highest levels of radioactivity were observed in liver, lung, kidney, small intestine and adrenal gland.
Acknowledgements
The authors would like to thank Dr. Bachir Latli for synthesis and purification of [14C]-faldaprevir. We also thank Drs. Jeff Duggan, Donald Tweedie, and Yongmei Li for their valuable input. The in-life part of mass balance study and most metabolite profiling and identification was carried out at XenoBiotic Laboratories, Plainsboro, NJ. The in-life tissue distribution study and QWBA analysis were conducted by Covance Laboratories Inc., Madison, WI.