Michael Merz

Self-employed

Background Drug‐induced liver injury (DILI) is a major concern for oncology drugs in clinical practice and under development. Monitoring cancer patients for hepatotoxicity is challenging as these patients may have abnormal liver tests pre‐treatment or on‐study for many reasons including liver injury due to past oncology treatments, hepatic metastas...

Background: Management of side effects in clinical trials has to balance generation of meaningful data with risk for patients. A toxicity area requiring detailed management guidelines is drug-induced liver injury (DILI). In oncology trials, patients are often included despite baseline liver test abnormalities, for whom there is no consensus yet on...

Background and aims We hypothesized that a drug’s clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multi...

Background Drug‐induced liver injury (DILI) requires accurate case adjudication, with expert opinion being the current best practice. Aim We utilised a novel DILI causality assessment tool (DILI‐CAT), which uses drug‐specific liver injury phenotypes, to examine potential DILI in early phase ximelagatran clinical development. Methods We conducted...

Objective: We hypothesized that a drug-characteristic DILI-phenotype could be defined and be used to develop a computer-assisted DILI causality assessment-tool (DILI-CAT) Design: A drug-specific DILI-phenotype was developed for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and polygonum multiflorum using data from published case series...

Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when an individual is exposed to toxic doses of some compounds or as an unpredictable event with many drugs in common use. Drugs can be harmful to the liver in susceptible individuals owing to genetic and environmental ris...

The diagnosis and management of drug‐induced liver injury (DILI) remains a challenge in clinical trials in drug development. The qualification of emerging biomarkers capable of predicting DILI soon after the initiation of treatment, differentiating DILI from underlying liver disease, identifying the causal entity, and assigning appropriate treatmen...

Background Liver biomarkers alanine aminotransferase (ALT) and bilirubin in patients with hepatitis are above the healthy volunteer reference range (HVRR) at baseline (prior to receiving the clinical trial medication). Discussions continue as how to best distinguish drug-induced liver injury in patients with abnormal baseline values participating i...

Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of 14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n = 192 and n = 81), subjects who safely took poten...

Background There is a clear need for better biomarkers of drug-induced-liver-injury (DILI). Aims We aimed to evaluate the possible prognostic value of ActiTest and FibroTest proteins apoliprotein-A1, haptoglobin and alpha-2-macroglobulin, in patients with DILI. Methods We analyzed cases and controls included in the IMI-SAFE-T-DILI European projec...

Characteristics 154 DILI. (DOCX)

Repeated ApoA1 HAPTO A2M. (DOCX)

Groups of CoAuthors. (DOCX)

Anova 6 drugs and others 154 included cases. (DOCX)

Data between 4 subpopulations. (DOCX)

Anova 81 cases 3 tests 6 drugs. (DOCX)

Data set ApoA1 haptoglobin. (XLSX)

Introduction: Data incompleteness in pharmacovigilance (PV) health records limits the use of current causality assessment methods for drug-induced liver injury (DILI). In addition to the inherent complexity of this adverse event, identifying cases of high causal probability is difficult. Objective: The aim was to evaluate the performance of an i...

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither sp...

Bile acid research has gained great momentum since the role of bile acids as key signaling molecules in the enterohepatic circulation was discovered. Their physiological function in regulating their own homeostasis, as well as energy and lipid metabolism make them interesting targets for the pharmaceutical industry in the context of diseases such a...

The somatostatin analogue octreotide can lead to hyperbilirubinemia without evidence of liver injury. Here we investigate whether octreotide inhibits the main sinusoidal/canalicular bilirubin carriers and whether it is a transport substrate. Octreotide showed the most potent inhibitory effect towards OATP1B1-mediated transport and weaker inhibition...

Background Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. Aim To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. Methods Double-blind, randomised, placebo-cont...

BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-c...

Drug-induced liver injury (DILI) is a potentially fatal adverse event with significant medical and economic impact. Many drugs, especially anti-infective, neurologic or pain-modifying substances, act as hepatotoxins. With cardiovascular toxicity, liver toxicity is one of the two leading causes for drug withdrawal from the market. The liver can be a...

Analysis of liver safety data has to be multivariate by nature and needs to take into account time dependency of observations. Current standard tools for liver safety assessment such as summary tables, individual data listings, and narratives address these requirements to a limited extent only. Using graphics in the context of a systematic workflow...

The FDA guidance for industry in the premarketing clinical evaluation of drug-induced liver injury (DILI) is the most specific regulatory guidance currently available and has been useful in setting standards for the great majority of clinical indications involving subjects with a low risk of liver disorders. However, liver safety assessment faces c...

A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. In a breakout session, workshop attendees discussed necessary data elements and standards for the accurate measurement of DILI risk associated with new therapeutic agents in clinical trials. There was agreement that in order...

Causality assessment is a critical step in establishing the diagnosis of drug induced liver injury (DILI) during drug development. DILI may resemble almost any type of liver disease, and often presents a serious challenge to clinical investigators and drug makers. The diagnosis of DILI is largely based upon a combination of a compatible clinical co...

The patient presented below gives us the opportunity to discuss challenges in the diagnosis of drug-induced liver injury in an era of increasing awareness of hepatitis E.

Biomarkers have become cornerstones of modern drug development, improving assessment of both efficacy and safety of new molecules. Use of graphical data exploration can help to maximize information output from biomarker data and improve efficiency of the data analysis process. The chapter describes a systematic workflow for interactive graphical da...

New biomarkers of drug-induced liver injury (DILI) are required in the clinic and in preclinical pharmaceutical evaluation. Liver-enriched microRNAs are promising serum biomarkers of acetaminophen-induced acute liver injury in mice. The utility of circulating microRNAs as biomarkers of human acute DILI is discussed in the context of correlation wit...

Introduction: Following a US National Academy of Sciences report in 2007 entitled "Toxicity Testing of the 21st Century: a Vision and a Strategy," significant advances within translational drug safety sciences promise to revolutionize drug discovery and development. The purpose of this review is to outline why investigative safety science is a com...

The importance of using translational safety biomarkers that can predict, detect and monitor drug-induced toxicity during human trials is becoming increasingly recognized. However, suitable processes to qualify biomarkers in clinical studies have not yet been established. There is a need to define clear scientific guidelines to link biomarkers to c...

In a monocentric, double-blind, randomized trial, we examined the safety and pharmacokinetic profile of a new, pasteurized, human tetanus immunoglobulin (P-HTIG). As part of the purification process, P-HTIG has undergone a heat treatment step (10 h at 60 degrees C) and the removal of Merthiolate. Forty-eight adults with a history of tetanus vaccina...

The SAFE-T consortium was one of the first projects established under the EUs Innovative Medicines Initiative (IMI), starting on June 15, 2009. SAFE-T is working to address the current lack of sensitive and specific clinical tests to diagnose and monitor drug-induced injury to the kidney, liver and vascular systems in man, which is a major hurdle i...