Drug rechallenge following drug-induced liver injury.

Drug-induced hepatocellular injury is identified internationally by alanine aminotransferase (ALT) levels equal to or exceeding 5× the upper limit of normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decrease by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT level of 3-5× ULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug-induced liver injury (DILI): antimicrobials; and central nervous system, cardiovascular and oncology therapeutics. Drugs associated with high rates of positive rechallenge exhibit multiple risk factors: daily dose >50 mg, an increased incidence of ALT elevations in clinical trials, immunoallergic clinical injury, and mitochondrial impairment in vitro. These drug factors interact with personal genetic, immune, and metabolic factors to influence positive rechallenge rates and outcomes. Drug rechallenge following drug-induced liver injury is associated with up to 13% mortality in prospective series of all prescribed drugs. In recent oncology trials, standardized systems have enabled safer drug rechallenge with weekly liver chemistry monitoring during the high-risk period and exclusion of patients with hypersensitivity. However, high positive rechallenge rates with other innovative therapeutics suggest that caution should be taken with rechallenge of high-risk drugs. CONCLUSION: For critical medicines, drug rechallenge may be appropriate when 1) no safer alternatives are available, 2) the objective benefit exceeds the risk, and 3) patients are fully informed and consent, can adhere to follow-up, and alert providers to hepatitis symptoms. To better understand rechallenge outcomes and identify key risk factors for positive rechallenge, additional data are needed from controlled clinical trials, prospective registries, and large health care databases. (Hepatology 2017;66:646-654).

Characterizing phenotypes and outcomes of drug-associated liver injury using electronic medical record data.

PURPOSE: To evaluate the incidence, phenotypes, and outcomes of drug-associated liver injury identified in electronic medical record (EMR) data using standardized criteria for drug-induced liver injury (DILI). METHODS: This retrospective cohort study used EMR data from a large integrated healthcare system. Study inclusion required 18 years of age or older, ≥1 prescription fill for any of 14 medications associated with hepatotoxicity between 1 January 2003 and 30 June 2009, and ≥12 months of membership prior to the drug exposure. Patients with underlying non-drug causes of liver injury were excluded to minimize capture of liver injury events unrelated to drugs. Drug-associated liver injuries were identified by liver chemistry elevations temporally associated with drug use based on standardized criteria for DILI. Cases were classified by clinical pattern and severity. Outcomes of liver transplant and all-cause and liver-related death were examined. RESULTS: A total of 1 053 979 drug exposures were identified in 601 125 patients. We identified 265 drug-associated liver injuries (32.8 per 100 000 persons) occurring in 250 patients. Isoniazid exhibited the highest incidence rate of 606 per 100 000 persons. Of the 265 cases, 41% were mild; 12% exhibited moderate drug-associated liver injury (with concomitant ALT ≥ 5× ULN and bilirubin ≥2× ULN); and 17% exhibited coagulopathy, ascites, encephalopathy, or other organ failure. Last, seven cases (3%) were associated with death, and there were no liver transplants. CONCLUSIONS: Study results align with earlier prospective studies, supporting the value of standardized methodology to identify drug-associated liver injury in the EMR. These methods can potentially enhance safety and clinical outcomes.

A pre-marketing ALT signal predicts post-marketing liver safety.

Drug induced liver injury during drug development is evidenced by a higher incidence of serum alanine aminotransferase (ALT) elevations in treated versus placebo populations and termed an "ALT signal". We sought to quantify whether an ALT signal in pre-marketing clinical trials predicted post-marketing hepatotoxicity. Incidence of ALT elevations (ALT ≥ 3 times upper limits normal [× ULN]) for drug and placebo of new chemical entities and approved drugs associated with hepatotoxicity was calculated using the Food and Drug Administration (FDA) website. Post-marketing liver safety events were identified using the FDA Adverse Event Reporting System (AERS). The association of FDA AERS signal score (EB05 ≥ 2) and excess risk of pre-marketing ALT elevation (difference in incidence of ALT ≥ 3× ULN in treated versus placebo) was examined. An ALT signal of ≥ 1.2% was significantly associated with a post-marketing liver safety signal (p ≤ 0.013) and a 71.4% positive predictive value. An absent ALT signal was associated with a high likelihood of post-marketing liver safety; negative predictive value of 89.7%. Daily drug dose information improved the prediction of post-marketing liver safety. A cut-off of 1.2% increase in ALT ≥ 3× ULN in treated versus placebo groups provides an easily calculated method for predicting post-marketing liver safety.

The evaluation of drug rechallenge: the casopitant Phase III program.

Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, is associated with 13% mortality in prospective series. Rechallenge generally results in much more rapid injury than the initial liver event. The neurokinin-1 antagonist casopitant or its placebo was administered cyclically with ondansetron and dexamethasone in two randomized chemotherapy-induced nausea and vomiting clinical trials in nearly 3000 subjects. Grade 3 ALT elevations were observed in up to 2% of subjects receiving casopitant or placebo treatment. Similar rates of positive rechallenge were observed in the casopitant 8/29 (28%) and placebo groups 2/8 (25%), with no Grade 4 ALT elevations, hypersensitivity or liver-related serious adverse events. Publishing available rechallenge data (positive and negative) will advance our clinical understanding. Rechallenge should only be considered when the potential drug benefit exceeds the risk.

Drug-induced liver injury following positive drug rechallenge.

Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, can lead to serious or fatal liver injury. A retrospective review of a large pharmaceutical safety database was conducted to assess clinical outcomes of positive drug rechallenge following possible drug-induced liver injury. Positive rechallenge with suspect drug was reported in 770 of 36,795 hepatic adverse events. A total of 88 cases met inclusion criteria for analysis. Mean age was 44 years (range 0.5-83) and 56% were male. A broad spectrum of suspect drugs were identified. Many patients exhibited hepatitis symptoms or jaundice on the initial and rechallenge liver event. Twelve patients (14%) exhibited clinically worrisome severe hepatocellular injury and jaundice on either initial or rechallenge event and two died, reflecting a 2.3% fatality rate in those with positive rechallenge. The two fatalities developed severe hepatocellular injury with jaundice only upon rechallenge. Liver injury recurred in most rechallenges. Improved identification and communication of possible drug-induced liver injury is needed to avoid potentially serious and/or fatal drug rechallenges. Clinicians should generally avoid such rechallenges.

Consumers Better Understand and Prefer Simplified Written Drug Information: An Evaluation of 2 Novel Formats Versus the Current CMI.

Patients in the United States receive multiple forms of written drug information with their prescription medicines. This study solicited consumers' preferences about formatting of information, their motivation to read drug information, and their ability to navigate and understand the information. A 3 × 3 study design was used in which 3 prototypes for 3 prescription drugs, ORTHO TRI-CYCLENTM (norgestimate/ethinyl estradiol), COUMADINTM (warfarin sodium), and PARNATETM (tranylcypromine sulfate), were evaluated. The prototypes included 2 novel formats ("new" and "bubble") and the "current" format that patients now commonly receive with their prescriptions. A total of 105 consumers participated in the study. Consumers correctly answered more questions about the medicine when presented with a new (70%-95%) or a bubble prototype (83%-92%) than with the current format (53%-74%). All attributes scored higher with both prototypes compared with the current format. However, in terms of overall preference, consumers favored the new prototype and indicated that they would be more motivated to read it. Consumers also reported that simple icons assisted them in finding important information. The new and bubble prototypes were favored by participants more than the current format. Key attributes preferred by consumers must be considered as new formats for patient medication information are developed.

Monitoring liver safety in drug development: the GSK experience.

To promptly identify and evaluate liver safety events, an evidence-based liver safety system was created for global Phase I-III clinical trials. The goals of this system included improving clinical trial subject safety, expanding information on liver safety events, and improving data quality across studies by establishing and communicating: Two different algorithms for liver stopping criteria were developed. The most stringent criteria were selected for healthy volunteers in Phase I studies, where no treatment benefit is anticipated and clinical safety data are limited. With an interest in assessing potential liver "tolerance" or adaptation with accruing safety information, slightly higher liver chemistry thresholds were set for Phase II-III studies. This paper will describe the importance of liver safety in drug development, laboratory tests used to monitor liver safety, the rationale for selected liver chemistry subject stopping criteria, and implementation of this safety system.