Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials.

RATIONALE & OBJECTIVE: Tolvaptan is associated with risk of drug-induced liver injury when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE trial and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted. STUDY DESIGN: Analysis of safety data from prospective clinical trials of tolvaptan. SETTING & PARTICIPANTS: Multicenter clinical trials including more than 2,900 tolvaptan-treated participants, more than 2,300 with at least 18 months of drug exposure. INTERVENTION: Tolvaptan administered twice daily in split-dose regimens. OUTCOMES: Frequency of liver enzyme level increases detected by regular laboratory monitoring. RESULTS: In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38 of 681 [5.6%] vs 8 of 685 [1.2%]) experienced alanine aminotransferase level increases to >3× the upper limit of normal (ULN), similar to TEMPO 3:4 (40 of 957 [4.4%] vs 5 of 484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent alanine aminotransferase level increases to >3× ULN and total bilirubin increases to >2× ULN ("Hy's Law" laboratory criteria). Based on the expanded dataset, liver enzyme increases most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Increased levels returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial drug-induced liver injury episode, with return of liver enzyme level increases in 30; 1 additional participant showed a clinical "adaptation" after the initial episode, with resolution of the enzyme level increases despite continuation of tolvaptan. LIMITATIONS: Retrospective analysis. CONCLUSIONS: The absence of Hy's Law cases in REPRISE and the long-term extension trial support monthly liver enzyme monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter to detect and manage enzyme level increases, as is recommended on the drug label. FUNDING: Otsuka Pharmaceutical Development & Commercialization, Inc. TRIAL REGISTRATION: Trials included in the dataset were registered at ClinicalTrials.gov with study numbers NCT00428948 (TEMPO 3:4), NCT01214421 (TEMPO 4:4), NCT02160145 (REPRISE), and NCT02251275 (long-term extension).

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors.

BACKGROUND: Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib. MATERIALS, AND METHODS: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. RESULTS: In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. CONCLUSION: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. IMPLICATIONS FOR PRACTICE: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.

Real-world safety of palbociclib in breast cancer patients in the United States: a new user cohort study.

BACKGROUND: There is limited real-world safety information on palbociclib for treatment of advanced stage HR+/HER2- breast cancer. METHODS: We conducted a cohort study of breast cancer patients initiating palbociclib and fulvestrant from February 2015 to September 2017 using the HealthCore Integrated Research Database (HIRD), a longitudinal claims database of commercial health plan members in the United States. The historical comparator cohort comprised patients initiating fulvestrant monotherapy from January 2011 to January 2015. Propensity score matching and Cox regression were used to estimate hazard ratios for various safety events. For acute liver injury (ALI), additional analyses and medical record validation were conducted. RESULTS: There were 2445 patients who initiated palbociclib including 566 new users of palbociclib-fulvestrant, and 2316 historical new users of fulvestrant monotherapy. Compared to these historical new users of fulvestrant monotherapy, new users of palbociclib-fulvestrant had a greater than 2-fold elevated risk for neutropenia, leukopenia, thrombocytopenia, stomatitis and mucositis, and ALI. Incidence of anemia and QT prolongation were more weakly associated, and incidences of serious infections and pulmonary embolism were similar between groups after propensity score matching. After adjustment for additional ALI risk factors, the elevated risk of ALI in new users of palbociclib-fulvestrant persisted (e.g. primary ALI algorithm hazard ratio (HR) = 3.0, 95% confidence interval (CI) = 1.1-8.4). CONCLUSIONS: This real-world study found increased risks of several adverse events identified in clinical trials, including neutropenia, leukopenia, and thrombocytopenia, but no increased risk of serious infections or pulmonary embolism when comparing new users of palbociclib-fulvestrant to fulvestrant monotherapy. We observed an increased risk of ALI, extending clinical trial findings of significant imbalances in grade 3/4 elevations of alanine aminotransferase (ALT).

Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.

Hepatotoxicty of Agents Used in the Management of Inflammatory Bowel Disease: a 2020 Update.

PURPOSE OF REVIEW: As treatment options for inflammatory bowel disease (IBD) continue to expand, the opportunity for hepatotoxicity remains a clinical concern. This review looks to update the current literature on drug-induced liver injury (DILI) and liver-related complications from current and emerging treatments for Crohn's disease (CD) and ulcerative colitis (UC). RECENT FINDINGS: An extensive literature review on currently used medications to treat IBD and their liver-related side effects that includes mesalamine, thiopurines, certain antibiotics, methotrexate, anti-TNF agents including recently introduced biosimilars, anti-integrin therapy, anti-IL 12/IL 23 therapy, and small molecule JAK inhibitors. Hepatotoxicity remains an important clinical issue when managing patients with IBD. Clinicians need to remain aware of the potential for liver-related adverse events with various medication classes and adjust their clinical monitoring as appropriate based on the agents being used.

Significant Variation in the Detection Rates of Proximal Serrated Polyps Among Academic Gastroenterologists, Community Gastroenterologists, and Colorectal Surgeons in a Single Tertiary Care Center.

INTRODUCTION: Recent studies have demonstrated that the protective effect of colonoscopy against colorectal cancer is lower in the proximal colon. Proximal serrated polyps, including sessile serrated adenomas and proximal hyperplastic polyps, can be frequently missed and pose a risk of interval cancers. AIM: To investigate the overall adenoma detection rate (ADR) and the proximal serrated polyp detection rate (PSPDR) among academic gastroenterologists, community gastroenterologists, and colorectal surgeons from a single institution, all of whom have received formal training in colonoscopy during their fellowship. METHODS: All complete screening colonoscopies for patients aged 50 or older with a good to excellent bowel preparation performed by different endoscopists at Medstar Washington Hospital Center (Washington, DC) from July 2015 to December 2017 were reviewed. Pathology reports of the resected polyps were manually reviewed. RESULTS: A total of 2850 screening colonoscopies meeting the inclusion criteria were performed by 18 endoscopists (6 academic, 7 community, and 5 colorectal surgeons). There was no significant difference in the mean ADR among the three groups of endoscopists: academic gastroenterologists, community gastroenterologists, and colorectal surgeons (40.3% vs 36.0% vs 39.6%, respectively). However, academic gastroenterologists had a significantly higher PSPDR compared to community gastroenterologists or colorectal surgeons (12.3% vs 5.4% vs 4.5%, respectively, ANOVA p = 0.006). CONCLUSION: Our novel data show that academic gastroenterologists had a significantly higher PSPDR compared to community gastroenterologists or colorectal surgeons despite a comparable overall ADR among the three groups. PSPDR may be considered as an important quality indicator for colonoscopy, apart from ADR.

The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond.

Drug-induced liver injury (DILI) remains a leading reason why new compounds are dropped from further study or are the subject of product warnings and regulatory actions. Hy's Law of drug-induced hepatocellular jaundice causing a case-fatality rate or need for transplant of 10% or higher has been validated in several large national registries, including the ongoing, prospective U.S. Drug-Induced Liver Injury Network. It serves as the basis for stopping rules in clinical trials and in clinical practice. Because DILI can mimic all known causes of acute and chronic liver disease, establishing causality can be difficult. Histopathologic findings are often nonspecific and rarely, if ever, considered pathognomonic. A daily drug dose >50-100 mg is more likely to be hepatotoxic than does <10 mg, especially if the compound is highly lipophilic or undergoes extensive hepatic metabolism. The quest for a predictive biomarker to replace alanine aminotransferase is ongoing. Markers of necrosis and apoptosis such as microRNA-122 and keratin 18 may prove useful in identifying patients at risk for severe injury when they initially present with a suspected acetaminophen overdose. Although a number of drugs causing idiosyncratic DILI have HLA associations that may allow for pre-prescription testing to prevent hepatotoxicity, the cost and relatively low frequency of injury among affected patients limit the current usefulness of such genome-wide association studies. Alanine aminotransferase monitoring is often recommended but has rarely been shown to be an effective method to prevent serious DILI. Guidelines on the diagnosis and management of DILI have recently been published, although specific therapies remain limited. The LiverTox Web site has been introduced as an interactive online virtual textbook that makes the latest information on more than 650 agents available to clinicians, regulators, and drug developers alike.

Hepatic decompensation likely attributable to simeprevir in patients with advanced cirrhosis.

BACKGROUND: Hyperbilirubinemia is a common side effect of protease inhibitors used to treat chronic hepatitis C (HCV), and most patients do not experience without clinically overt hepatotoxicity. The safety of second-wave protease inhibitors, including simeprevir, has not been well studied in patients with advanced cirrhosis. MATERIALS & METHODS: We report two cases of suspected drug-induced liver injury leading to hepatic decompensation in patients with advanced HCV cirrhosis treated with the combination of simeprevir and sofosbuvir on a compassionate basis. Both patients developed marked hyperbilirubinemia out of proportion to their aminotransferases, despite clearance of hepatitis C RNA. RUCAM scoring was probable and possible, respectively. While other factors may have contributed to the liver injury, including infection and concurrent administration of other medications, we believe that the potentially deleterious hepatic effects of simeprevir on transporters or other key functional components were the main reason for their decompensation. CONCLUSIONS: Protease inhibitors should be used with caution, if at all, in patients with cirrhosis, especially in those with the most advanced disease. We await newer, safer, direct-acting antiviral therapies for such patients, especially those on our transplant list.

Clinical outcomes with metformin use in diabetic patients with compensated cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Previous studies have demonstrated a beneficial effect of metformin in patients with cirrhosis, but no improvement in liver histology. AIM: To investigate the impact of metformin on mortality and hepatic decompensation in people with diabetes with compensated cirrhosis. METHODS: Medline, Embase and Cochrane databases were searched from inception to February 2023 for studies reporting results regarding the impact of metformin on all-cause mortality and hepatic decompensation in people with diabetes with compensated cirrhosis. The risk of bias was assessed by ROBINS-I Cochrane tool. R software 4.3.1 was used for all analyses. RESULTS: Six observational studies were included in the final analysis. Metformin use was associated with reduced all-cause mortality or liver transplantation [hazard ratio (HR): 0.55; 95% confidence interval (CI) 0.37-0.82], while no benefit was shown in the prevention of hepatic decompensation (HR: 0.97; 95% CI: 0.77-1.22). In the subgroup analysis, metformin use was associated with reduced all-cause mortality or liver transplantation (HR: 0.50; 95% CI 0.38-0.65) in patients with metabolic-associated steatohepatitis cirrhosis, while two studies reported no survival benefit in patients with cirrhosis due to hepatitis C (HR: 0.39; 95% CI 0.12-1.20). CONCLUSION: Metformin use is associated with reduced all-cause mortality, but not with the prevention of hepatic decompensation in people with diabetes with compensated cirrhosis. The mortality benefit is most likely driven by better diabetes and cardiovascular health control.

Consensus Guidelines: Best Practices for the Prevention, Detection and Management of Hepatitis B Virus Reactivation in Clinical Trials with Immunosuppressive/Immunomodulatory Therapy.

Hepatitis B virus reactivation (HBVr) during and after immunosuppressive/immunomodulatory (IS/IM) therapy is associated with significant morbidity and mortality, including hepatic decompensation and acute liver failure. The risk of HBVr with IS/IM has been heterogeneous and often unpredictable. As a result, patients with active or previous HBV infection are often excluded from clinical drug trials of such agents. Thorough screening for HBV infection, antiviral prophylaxis, and careful monitoring for HBVr have proven to be effective in reducing the rate of HBVr and improving its outcome in the context of IS/IM. Therefore, safe enrollment and management of certain HBV-marker-positive patients in clinical trials is possible. There is a great, unmet need for consistent, evidence-based recommendations for best practices pertaining to enrollment, monitoring, and management of HBVr in clinical trial participants receiving IS/IM. The aim of these consensus guidelines is to provide a step-by-step blueprint to safely enroll, monitor and manage the patient with inactive chronic or resolved HBV in IS/IM clinical trials from the time of screening through to the end of post-treatment follow up.

Drug-Induced Liver Injury in the Elderly: Consensus Statements and Recommendations from the IQ-DILI Initiative.

The elderly demographic is the fastest-growing segment of the world's population and is projected to exceed 1.5 billion people by 2050. With multimorbidity, polypharmacy, susceptibility to drug-drug interactions, and frailty as distinct risk factors, elderly patients are especially vulnerable to developing potentially life-threatening safety events such as serious forms of drug-induced liver injury (DILI). It has been a longstanding shortcoming that elderly individuals are often a vulnerable population underrepresented in clinical trials. As such, an improved understanding of DILI in the elderly is a high-priority, unmet need. This challenge is underscored by recent documents put forward by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) that encourage data collection in the elderly and recommend improved practices that will facilitate a more inclusive approach. To establish what is already known about DILI in the elderly and pinpoint key gaps of knowledge in this arena, a working definition of "elderly" is required that accounts for both chronologic and biologic ages and varying states of frailty. In addition, it is critical to characterize the biological role of aging on liver function, as well as the different epidemiological factors such as polypharmacy and inappropriate prescribing that are common practices. While data may not show that elderly people are more susceptible to DILI, DILI due to specific drugs might be more common in this population. Improved characterization of DILI in the elderly may enhance diagnostic and prognostic capabilities and improve the way in which liver safety is monitored during clinical trials. This summary of the published literature provides a framework to understand and evaluate the risk of DILI in the elderly. Consensus statements and recommendations can help to optimize medical care and catalyze collaborations between academic clinicians, drug manufacturers, and regulatory scientists to enable the generation of high-quality research data relevant to the elderly population.

Liver biopsy for assessment of suspected drug-induced liver injury in metabolic dysfunction-associated steatohepatitis clinical trials: Expert consensus from the Liver Forum.

BACKGROUND: Causality assessment of suspected drug-induced liver injury (DILI) during metabolic dysfunction-associated steatohepatitis (MASH) clinical trials can be challenging, and liver biopsies are not routinely performed as part of this evaluation. While the field is moving away from liver biopsy as a diagnostic and prognostic tool, information not identified by non-invasive testing may be provided on histology. AIM: To address the appropriate utilisation of liver biopsy as part of DILI causality assessment in this setting. METHODS: From 2020 to 2022, the Liver Forum convened a series of webinars on issues pertaining to liver biopsy during MASH trials. The Histology Working Group was formed to generate a series of consensus documents addressing these challenges. This manuscript focuses on liver biopsy as part of DILI causality assessment. RESULTS: Expert opinion, guidance and recommendations on the role of liver biopsy as part of causality assessment of suspected DILI occurring during clinical trials for a drug(s) being developed for MASH are provided. Lessons learned from prior MASH programs are reviewed and gaps identified. CONCLUSIONS: Although there are no pathognomonic features, histologic evaluation of suspected DILI during MASH clinical trials may alter patient management, define the pattern and severity of injury, detect findings that favour a diagnosis of DILI versus MASH progression, identify prognostic features, characterise the clinicopathological phenotype of DILI, and/or define lesions that influence decisions about trial discontinuation and further development of the drug.

Drug-induced liver injury in the elderly.

Historically, the elderly have been considered to be at increased risk for drug-induced liver injury (DILI). Animal studies have demonstrated changes in hepatic physiology that affect drug metabolism in the aging liver; however, there is no evidence that this leads to any appreciable deterioration of liver function in healthy older humans. Updated data from international DILI registries give us pause to consider whether the elderly are truly at increased risk to develop hepatic injury. Instead, hepatotoxicity in the elderly appears to be more a function of drug exposure, polypharmacy and drug-drug interactions. Isoniazid and benoxaprofen are the only two agents with a well-studied correlation between increasing age and risk of DILI. Nevertheless, given the increasing proportion of patients over age 65 in the U.S. and abroad, the influence of age on the risk of DILI is the focus of this review.

Polypharmacy and comorbidity are associated with a lower early virologic response in hepatitis C patients treated with first generation protease inhibitor triple therapy: a preliminary analysis.

BACKGROUND AND AIMS: The protease inhibitors (PIs) boceprevir and telaprevir are currently standard treatment as part of triple therapy regimens (TTx) for chronic HCV genotype 1 (GT1) patients. In this preliminary analysis, we have compared demographic variables, polypharmacy, and Charlson's comorbid index (CCI) with Rapid Virological Response (RVR) and extended RVR (eRVR) rates in HCV GT1 patients receiving PI containing TTx. METHODS: Retrospective descriptive cohort study. RESULTS: Among 74 HCV patients (46 M, 28 F; age: 54.43 ± 9.52 years; African Americans: 59.5 %) in this initial analysis, 44 % achieved RVR. All these RVR patients also achieved eRVR. Patients achieving RVR and eRVR were 50 ± 11.7 (mean ± SD) years old, compared to 58 ± 5.2 years without an RVR (p < 0.005). The average number of medications taken by patients achieving RVR and eRVR was 5 ± 2.7 compared to 9.24 ± 3.4 in patients not achieving RVR and eRVR (p < 0.005). Twenty-five percent of patients who were not on CYP3A4 inhibitors had an RVR and eRVR compared to 63.2 % who were taking CYP3A4 inhibitors (p = 0.001). Patients achieving RVR and eRVR had a lower CCI (1.61 ± 1.37) compared to those not achieving RVR and eRVR (2.8 ± 2.7; p = 0.02). Multivariate analysis also revealed a significant correlation between increased polypharmacy and CCI with lower RVR and eRVR rates. CONCLUSIONS: These preliminary treatment data demonstrate that increased polypharmacy and higher degrees of comorbidity decrease RVR and eRVR rates among patients receiving first generation PI-containing TTx regimens.

The predictive value of liver tests for the presence of liver metastases.

Aim: To analyze the predictive value of biochemical liver tests in patients with malignant melanoma, breast, colorectal or lung cancers at the time of diagnosis of liver metastases. Methods: A retrospective review of patients with the above-mentioned solid tumors at MedStar Georgetown University Hospital from 2016-2020. Results: The highest optimal cutoff according to sensitivity and specificity for the presence of liver metastases was for AST ≥1.5 × ULN for melanoma, lung, and breast cancers and ≥2 × ULN for colorectal cancer, ALT ≥1.25 × ULN for melanoma, breast and colorectal cancers and ≥1.5 × ULN for lung cancer, and ALP ≥1.5 × ULN for melanoma, breast and colorectal cancers. Conclusion: Using thresholds of liver enzymes above the ULN may improve the diagnostic accuracy for the presence of liver metastases.

The Metreleptin Effectiveness and Safety Registry (MEASuRE): concept, design and challenges.

BACKGROUND: Metreleptin, a recombinant analog of human leptin, is an approved therapy, adjunct to diet, to treat the metabolic complications of leptin deficiency in patients with lipodystrophy - a group of rare diseases characterized by a paucity of adipose tissue. MEASuRE (Metreleptin Effectiveness And Safety Registry) is a post-authorization, voluntary registry that gathers long-term safety and effectiveness data on metreleptin. Here, we present the aims and evolution of MEASuRE. METHODS: MEASuRE was established to collect data from patients receiving commercially supplied metreleptin in the United States (US) and European Union (EU). MEASuRE aims to determine the incidence and severity of safety events and describe the clinical characteristics and therapeutic outcomes in the metreleptin-treated population. A key feature of MEASuRE is that it accumulates data from different sources to meet post-authorization objectives. US data are received directly from treating physicians via a contract research organization-mediated electronic data capture system. In the EU, data are received via the European Registry of Lipodystrophies managed by the European Consortium of Lipodystrophies (ECLip), a platform established by researchers and physicians to advance the knowledge of lipodystrophy. MEASuRE complies with applicable regulatory requirements governing privacy, and the storage, management, and access of data. RESULTS: Leveraging processes, infrastructure, and data from the ECLip registry presented several challenges that were addressed during MEASuRE's development, including the expansion of the ECLip registry to accommodate MEASuRE-specific data elements, extensive data matching processes to ensure data consistency regardless of source, and rigorous data validation following the amalgamation of global data. Through the support of ECLip, MEASuRE is now a fully operational registry with the capacity for gathering and integrating standardized US- and EU-derived data. As of 31st October 2022, 15 US and four EU sites have participated in the MEASuRE, enrolling 85 patients globally. CONCLUSIONS: Our experiences show that a post-authorization product registry can be successfully integrated into an existing patient registry. We propose that, through collaboration with existing registries and use of their established resources, patient enrolment timelines and data collection for new registries can be expedited. The learnings presented here may be applicable to other registries with similar objectives. TRIAL REGISTRATION: NCT02325674; Registered 25 December 2014 - Retrospectively registered'. https://clinicaltrials.gov/ct2/show/NCT02325674 .

Clinical Significance of Transient Asymptomatic Elevations in Aminotransferase (TAEAT) in Oncology.

Monitoring for liver injury remains an important aspect of drug safety assessment, including for oncotherapeutics. When present, drug-induced liver injury may limit the use or result in the discontinuation of these agents. Drug-induced liver injury can exhibit with a wide spectrum of clinical and biochemical manifestations, ranging from transient asymptomatic elevations in aminotransferases (TAEAT) to acute liver failure. Numerous oncotherapeutics have been associated with TAEAT, with published reports indicating a phenomenon in which patients may be asymptomatic without overt liver injury despite the presence of grade ≥3 aminotransferase elevations. In this review, we discuss the occurrence of TAEAT in the context of oncology clinical trials and clinical practice, as well as the clinical relevance of this phenomenon as an adverse event in response to oncotherapeutics and the related cellular and molecular mechanisms that may underlie its occurrence. We also identify several gaps in knowledge relevant to the diagnosis and the management of TAEAT in patients receiving oncotherapeutics, and identify areas warranting further study to enable the future development of consensus guidelines to support clinical decision-making.

Highlights of the drug-induced liver injury literature for 2021.

INTRODUCTION: In 2021, over 3,000 articles on Drug-Induced Liver Injury (DILI) were published, nearly doubling the annual number compared to 2011. This review selected DILI articles from 2021 we felt held the greatest interest and clinical relevance. AREAS COVERED: A literature search was conducted using PubMed between 1 March 2021 and 28 February 2022. 86 articles were included. This review discusses new and established cases of hepatotoxins, including new FDA approvals and COVID-19 therapeutics. Developments in biomarkers and causality assessment methods are discussed. Updates from registries are also explored. EXPERT OPINION: DILI diagnosis and prognostication remain challenging. Roussel Uclaf Causality Assessment Method (RUCAM) is the best option for determining causality and has been increasingly accepted by clinicians. Revised Electronic Causality Assessment Method (RECAM) may be more user-friendly and accurate but requires further validation. Quantitative systems pharmacology methods, such as DILIsym, are increasingly used to predict hepatotoxicity. Oncotherapeutic agents represent many newly approved and described causes of DILI. Such hepatotoxicity is deemed acceptable relative to the benefit these drugs offer. Drugs developed for non-life-threatening disorders may not show a favorable benefit-to-risk ratio and will be more difficult to approve. As the COVID-19 landscape evolves, its effect on DILI deserves further investigation.

Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non-alcoholic Steatohepatitis.

High saturated fat diets have been shown to raise blood levels of cholecystokinin (CCK) and induce nonalcoholic steatohepatitis (NASH). CCK receptors are expressed on stellate cells and are responsible for hepatic fibrosis when activated. The purpose of this study was to test the safety and dose of a CCK receptor antagonist, proglumide, in human participants with NASH. An open-label single ascending dose study was conducted in 18 participants with clinical NASH based upon steatosis by liver ultrasound, elevated hepatic transaminases, and a component of the metabolic syndrome. Three separate cohorts (N = 6 each) were treated with oral proglumide for 12 weeks in a sequential ascending fashion with 800 (Cohort 1), 1,200 (Cohort 2), and 1,600 (Cohort 3) mg/day, respectively. Blood hematology, chemistries, proglumide levels, a biomarker panel for fibrosis, and symptom surveys were determined at baseline and every 4 weeks. Abdominal ultrasounds and transient elastography utilizing FibroScan were obtained at baseline and at Week 12. Proglumide was well tolerated at all doses without any serious adverse events. There was no change in body weight from baseline to Week 12. For Cohorts 1, 2, and 3, the median percent change in alanine aminotransferase was 8.42, -5.05, and -22.23 and median percent change in fibrosis score by FibroScan was 8.13, -5.44, and -28.87 (kPa), respectively. Hepatic steatosis as measured by controlled attenuation parameter score significantly decreased with proglumide, (P < 0.05). Blood microRNA biomarkers and serum 4-hydroxyproline were consistent with decreased fibrosis at Week 12 compared with baseline. These findings suggest proglumide exhibits anti-inflammatory and anti-fibrotic properties and this compound is well tolerated in participants with NASH.