Biotransformation and mass balance of faldaprevir, a hepatitis C NS3/NS4 protease inhibitor in rats

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 t_1/2 of plasma radioactivity was 1.75 h (males) and 1.74 h (females). Corresponding AUC_0–∞, CL and V_ss 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, t_1/2 and AUC_0–∞ 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.

• LC/MS
• metabolite identification
• pharmacokinetics
• QWBA
• radiolabeled

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.