Cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV genotype 1 NS3/4A protease inhibitor

Abstract

1. The present study describes the cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV protease inhibitor currently in phase III clinical trials.

2. BI 201335 showed a good Caco-II permeability (8.7 × 10⁻⁶ cm/sec) and in vitro metabolic stability (predicted hepatic clearence (CL_hep) <19% Q_h in all species tested).

3. Single dose PK revealed a clearance of 17, 3.0 and 2.6 mL/min/kg in rat, monkey and dog respectively, with a corresponding oral bioavailability of 29.1, 25.5 and 35.6%.

4. Comparative plasma and liver PK profile in rodents showed a high liver Kp in the rat (42-fold), suggesting high target tissue distribution.

5. Simple allometry based on animal PK predicted a human oral CL/F of 168 mL/min, within two-fold of the observed value (118 mL/min) at 240 mg in healthy volunteers.

6. Allometry of volume of distribution generated a low exponent of 0.59, and a much lower predicted Vss/F (5-fold less than observed). Several different approaches of Vss/F prediction were evaluated and compared with the value observed in human. The averaged Vss/F from preclinical animals provides the best estimation of the observed human value (169 L vs. 175 L).

7. Corresponding human “effective” t_1/2 values were also compared. The predicted human t_1/2 based on the CL from allometry with metabolic corrections and the averaged animal Vss represented the best estimation of the clinical data (12.1 vs. 17.2 hr).

8. The present study demonstrated that the good preclinical ADMEPK profile of BI 201335 is consistent with that observed in the clinic. While preclinical data accurately predicted the human CL, the prediction of human Vss seems to be more challenging. The averaged Vss/F from all tested preclinical animals provided the best prediction of human Vss and the resulting “effective” t_1/2.

Keywords::

• ADMEPK
• HCV protease
• human PK prediction

Acknowledgements

The authors would like to thank all members in the BI Canada HCV protease inhibitor project team for their contributions in making this study possible. In particular, we’d like to acknowledge the contribution from Miss Joelle Batonga, and Mr. Serge Bourg for their contribution to some of the experiments.

Declaration of interest

The authors report no conflicts of interest.