Efficacy and Safety of Magnesium Isoglycyrrhizinate Injection in Patients With Acute Drug-induced Liver Injury

A Phase II Trial

Yongfeng Wang; Zhenghua Wang; Mengqiu Gao; Haijun Zhong; Chengwei Chen; Yang Yao; Zhongshun Zhang; Xia Zhang; Fujian Li; Jianzhong Zhang; Hong-Mei Gu; Yingxuan Chen; Jieting Tang; Wei Zhong; Minde Zeng; Yimin Mao

Disclosures

Liver International. 2019;39(11):2102-2111. 

In This Article

Abstract and Introduction

Abstract

Background: Drug-induced liver injury (DILI) is the most common reason for a drug to be withdrawn from the market. Apart from stopping the offending drug, no regimens are available for treating idiosyncratic DILI in clinical practice.

Methods: We carried out a randomized, double-blind, multidoses, active drug controlled, multicentre phase II trial to assess the safety and efficacy of the study drug, magnesium isoglycyrrhizinate (MgIG), as compared to tiopronin, a standard therapy for DILI in China. The primary outcome was the proportion of alanine aminotransferase (ALT) normalization at week 4 after study drug administration. Logistic regression was used to examine the odds of ALT normalization between low dose (Group A) and high dose (Group B) vs active control (Group C).

Results: One hundred and seventy-four eligible subjects were randomized and enrolled into three groups: 59 in group A, 56 in group B and 59 in group C. It was shown that group A and group B lowered ALT level even at early stage of study drug administration; when compared with Group C (61.02%), the proportions of ALT normalization at week 4 were significantly greater in Group A (84.75%, P = .0029) and Group B (85.71%, P = .0037) respectively. The results from the univariate logistic model showed that the odds of ALT normalized among subjects in Group A were about 3.6 times greater (OR = 3.55, 95% CI: 1.47–8.57, P = .0049) than subjects in Group C. Similar effect was observed among subjects in Group B (OR = 3.83, 95% CI: 1.54–9.55, P = .0039).

Conclusions: This trial provided preliminary evidence that MgIG is an effective and safe treatment for patients with acute DILI.

Introduction

Drug-induced liver injury (DILI) is the most common reason for a drug to be withdrawn from the market, with more than 900 drugs implicated in causing liver injury.[1,2] Some cases only have elevated hepatic enzymes, but others can be fatal or require liver transplantation. Acetaminophen overdose aside, N-Acetylcysteine (NAC) is the only recommended drug to treat adults with drug-induced early-stage acute liver failure (ALF) based in a post-hoc analysis of a randomized clinical trial.[3,4] Other drugs, such as silymarin, ursodeoxycholic and tiopronin, are commonly used to treat DILI but there is lack of evidence.[5–9] No other treatment than stopping the offending drug is available. However, discontinuation of the offending drug may sometimes interfere with the treatment of the patients' primary diseases such as cancer or tuberculosis.

Glycyrrhizin acid, extracted from the roots of the plant Glycyrrhiza glabra, inhibits liver cell injury in animal models and was initially used for treatment of chronic viral hepatitis in Japan in 1990s.[10] Magnesium isoglycyrrhizinate (MgIG) is the magnesium salt form of the saponin, isoglycyrrhizinate, a derivative of glycyrrhizic acid with potential anti-inflammatory, antioxidant and hepatoprotective activities.[11] Although the exact mechanism of action remains to be fully elucidated, MgIG may prevent or reduce hepatotoxicity through the scavenging of free radicals. This agent has been shown to reduce the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST)[12] in a small trial of patients with chemotherapy-induced liver damage. The current study was the first trial to explore efficacy and safety of MgIG in treating DILI among the Chinese population.

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