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Antiviral Res. 2019 Mar;163:149-155. doi: 10.1016/j.antiviral.2019.01.017. Epub 2019 Jan 31.

A randomized, proof-of-concept clinical trial on repurposing chlorcyclizine for the treatment of chronic hepatitis C.

Author information

1
Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: Christopher.koh@nih.gov.
2
The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA.
3
Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
4
Clinical Mass Spectrometry Core, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
5
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
6
Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: JakeL@bdg10.niddk.nih.gov.

Abstract

BACKGROUND & AIMS:

Chlorcyclizine HCl (CCZ) is a piperazine-class antihistamine with anti-hepatitis C virus (HCV) activity in vitro and in vivo. In a first-in-humans study for HCV, we evaluated the antiviral effects and safety of CCZ±ribavirin (RBV), characterized pharmacokinetic (PK) and viral kinetic (VK) patterns, and provide insights into CCZs mode of action against HCV.

METHODS:

Chronic HCV patients were randomized to CCZ (75 mg twice daily) or CCZ+weight-based RBV (1000/1200 mg daily) for 28 days. Therapy started with a loading dose of CCZ 150 mg ± RBV. Serial assessments of safety, liver tests, PK and VK markers were obtained.

RESULTS:

24 HCV patients were treated; 54% male, median age 56 years, median HCV RNA 6.30 log IU/ml, without baseline differences between groups. At the end of therapy, subjects treated with CCZ monotherapy did not show any significant or sustained reduction in viremia (p = 0.69), whereas 7/12 (58%) subjects treated with CCZ+RBV had a >3-fold decline in HCV RNA. Subjects who responded demonstrated monophasic (n = 2), biphasic (n = 2) and triphasic (n = 3) VK responses. Contrary to historical RBV monotherapy response, CCZ+RBV demonstrated a continued viral decline suggesting a possible synergistic effect of CCZ+RBV. Mathematical modeling predicts a median effectiveness of CCZ+RBV in blocking viral production (ε) of 59% (Interquartile range, IQR: 50%) and blocking infection (η) of 78% (IQR: 23%). Adverse events (AEs) were mild-moderate without treatment discontinuations for AEs.

CONCLUSIONS:

In this human pilot study, CCZ demonstrated some anti-HCV effects, mostly in combination with RBV. More potent CCZ derivatives with optimal PK features may be more suitable for future therapeutic development. ClinicalTrials.gov number: NCT02118012.

KEYWORDS:

Chlorcyclizine HCl; Hepatitis C; Mathematical modeling; Treatment; Viral kinetics

PMID:
30711416
PMCID:
PMC6402797
[Available on 2020-03-01]
DOI:
10.1016/j.antiviral.2019.01.017

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