A first-in-human, randomized, double-blind, placebo-controlled, single and multiple ascending oral dose study to assess the safety, tolerability, and pharmacokinetics of BZF961 with and without ritonavir in healthy adult volunteers

Abstract

Objective: Infection with hepatitis C virus is the leading indication for liver transplantation and most common cause of infectious disease-related mortality in the United States. BZF961 is a novel inhibitor of the hepatitis C virus NS3-4A protease.

Methods: This sequential, three part exploratory first-in-human study investigated the safety and pharmacokinetics of single and multiple ascending oral doses of BZF961 in healthy subjects. The first two parts were randomized, double-blind, placebo-controlled, time-lagged, single and multiple ascending oral dose segments. The third part analyzed the effect of ritonavir on BZF961 pharmacokinetics.

Results: BZF961 was generally safe and well-tolerated in single and multiple oral doses in healthy subjects. There were no deaths and no serious adverse events. The most common adverse events were nausea and other gastrointestinal symptoms. Co-administration of ritonavir with BZF961 was well tolerated and increased BZF961 exposure by up to 60-fold, as well as reduced the overall exposure variability.

Conclusions: BZF961 was generally safe and well-tolerated and its exposure was boosted by the co-administration of ritonavir.

Keywords:

• First-in-human
• ritonavir
• BZF961
• protease inhibitor

Transparency

Declaration of funding

This study was funded by Novartis Institutes for BioMedical Research.

Declaration of financial/other relationships

AB, SM, CTJ, KD, CLJ, and RAC are, or were at the time of the study, employees of and/or shareholders in Novartis Pharmaceutical Corp. JDA peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

This manuscript is dedicated to Dr. Stephen Youngberg (1946–2013).