Cases Of Drug-induced Liver Injury Research Articles

#1891 Evaluating the safety and effectiveness of Tolvaptan for management of adult Korean ADPKD patients (ESSENTIAL study): final report

Abstract Background and Aims Tolvaptan, a selective vasopressin V2 receptor antagonist, was first approved by Korean FDA in 2015 as a treatment option in autosomal dominant polycystic kidney disease (ADPKD). In order to prescribe Tolvaptan safely and effectively, we designed the phase 4 clinical trial among Korean ADPKD patients with chronic kidney disease (CKD) stage 1-3. Method Korean patients aged 19 to 50 with rapidly progressing ADPKD were enrolled in the study. The dose titration was performed every one week for a total of 4 weeks. The patient was prescribed Tolvaptan with the maximum tolerable dose up to 120 mg per day. A total duration of Tolvaptan prescription was 24 months. The primary outcome was the incidence of treatment emergent adverse events (TEAE) including drug-induced liver injury (DILI). The secondary outcomes were the annual mean percent change of total kidney volume (TKV) and the annual mean change of estimated glomerular filtration rate (eGFR). Results A total of 117 patients were included in the analysis. Mean age was 38.7 ± 8.4 years old and male were predominant (58.1%). The average TKV was 2066 ± 1094 mL and mean eGFR was 79.7 ± 27.7 mL/min/1.73 m2. Mean duration of Tolvaptan exposure was 1.7 ± 0.6 years and the average daily dose of Tolvaptan was 94.4 ± 24.1 mg/day. A total of 489 treatment-emergent adverse events (TEAE) occurred in 106 (90.6%) patients during study duration. The drug-induced liver injury and aquaresis-related adverse events were two most common adverse events. A total of 17 DILI cases (14.5%) occurred during the study period and mostly within 18-month period. However, liver enzymes were normalized after drug discontinuation The patients with previous history of liver disease as well as those who were prescribed higher dose of Tolvaptan demonstrated higher frequency of DILI. Mean growth rate of TKV after Tolvaptan treatment was 4.5 ± 0.5% and mean eGFR decline rate was -3.0 ± 0.39 mL/min/1.73 m2/year. Comparing with the predicted value from calculation, Tolvaptan attenuated both TKV growth and eGFR decline rate. Conclusion This study is the first post-marketing survey assessing the safety and efficacy of Tolvaptan in Korean ADPKD patients. The incidence of DILI was higher than the previous studies and especially in those with liver disease and higher Tolvaptan prescription dose. While Tolvaptan can effectively reduce TKV and attenuate eGFR decline, the clinicians should be aware of higher frequency of DILI among Korean population.

Underreporting Supplements: A Case of Drug-induced Liver Injury Due to a Testosterone Booster.

Acute liver injuries (ALIs) are caused by a wide range of etiologies, and determining the cause can often be challenging. Detailed history taking is essential in patients with liver injuries to promptly determine the underlying source of injury and for timely treatment and prognosis. A 27-year-old active duty man presented to the emergency department (ED) with jaundice. On medication reconciliation, he only reported taking acetaminophen for a recent upper respiratory infection. The patient had an ALI and was treated with N-acetyl cysteine for presumed acetaminophen toxicity. Initially, his liver-associated enzymes (LAEs) improved, but 2 weeks after discharge, he returned to the ED upon referral from ship medical for jaundice and worsening liver injury. Repeated query into the patient's history revealed that he was using a testosterone booster supplement for 6 months preceding initial hospitalization. After evaluation of other etiologies for liver injury returned negative, drug-induced liver injury from the testosterone booster was determined to be the underlying etiology. With discontinuation of the supplement, his liver injury improved. Hepatotoxicity is a major concern in supplement use; however, it is largely underreported. Supplements are often not recognized or reported as medications by patients, leading to failure to identify them as potential toxicants. This case highlights the importance of including supplement education and questioning in the evaluation of ALI and maintaining a high index of suspicion when other common etiologies of liver disease are negative.

RECAM-J 2023-Validation and development of the Japanese version of RECAM for the diagnosis of drug-induced liver injury.

The diagnosis of drug-induced liver injury (DILI) is challenging. We modified the revised electronic version of the Roussel Uclaf Causality Assessment Method (RUCAM) for the diagnosis of DILI (RECAM), the scoring system developed in US and Spanish cohorts in 2022, and developed RECAM-J 2023 to align with the clinical practice in Japan. In the current study, we introduce RECAM-J 2023 and verify its performance in the context of Japanese patients with DILI. After translation of RECAM into Japanese, modifications were made to develop RECAM-J 2023 without any alteration to the scores. To examine the validity and performance of RECAM-J 2023, clinical information on DILI and non-DILI cases in Japan were retrospectively collected. The diagnosis of DILI was made by expert's decision. Then we scored each case using RECAM-J 2023, and calculated area under curve (AUC) values for identification for DILI. We collected data from 538 DILI and 128 non-DILI cases. The sum of highly probable (HP) and probable (PR) cases categorized by RECAM-J 2023 were only 206 (38%) in DILI cases. As the primary cause of low scores was the deduction with missing hepatitis virus markers, which is unlikely to be an issue in prospective applications, we rescored without these deductions. At this time, the sum of HP and PR was raised to 421 (78%). The AUCs of RECAM-J 2023 without deductions were 0.70 and 0.88 for identifying at least HP, and at least PR, respectively. RECAM-J 2023, when prospectively used without any missing hepatitis virus markers, provides acceptable performance for identifying at least PR DILI cases in Japanese daily clinical practice.

Drug-Induced Liver Injury in Pregnancy: The U.S. Drug-Induced Liver Injury Network Experience.

There are limited data on the causative agents and characteristics of drug-induced liver injury in pregnant individuals. Data from patients with drug-induced liver injury enrolled in the ongoing multicenter Drug-Induced Liver Injury Network between 2004 and 2022 and occurring during pregnancy or 6 months postpartum were reviewed and compared with cases of drug-induced liver injury in nonpregnant women of childbearing age. Among 325 individuals of childbearing age in the Drug-Induced Liver Injury Network, 16 cases of drug-induced liver injury (5%) occurred during pregnancy or postpartum. Compared with drug-induced liver injury in nonpregnant women, pregnancy-related drug-induced liver injury was more severe ( P <.05). One elective termination and three miscarriages were documented; there were no maternal deaths. We recommend that isoniazid for latent tuberculosis be deferred to the postpartum period whenever feasible and that β-blockers or calcium channel blockers rather than methyldopa be used for hypertension management during pregnancy.

Human Leucocyte Antigen Genetics in Idiosyncratic Drug-Induced Liver Injury with Evidence Based on the Roussel Uclaf Causality Assessment Method.

The human leucocyte antigen (HLA) allele variability was studied in cohorts of patients with idiosyncratic drug-induced liver injury (iDILI). Some reports showed an association between HLA genetics and iDILI, proposing HLA alleles as a potential risk factor for the liver injury. However, the strength of such assumptions heavily depends on the quality of the iDILI diagnosis, calling for a thorough analysis. Using the PubMed database and Google Science, a total of 25 reports of case series or single cases were retrieved using the terms HLA genes and iDILI. It turned out that in 10/25 reports (40%), HLA genetics were determined in iDILI cases, for which no causality assessment method (CAM) was used or a non-validated tool was applied, meaning the findings were based on subjective opinion, providing disputable results and hence not scoring individual key elements. By contrast, in most iDILI reports (60%), the Roussel Uclaf Causality Assessment Method (RUCAM) was applied, which is the diagnostic algorithm preferred worldwide to assess causality in iDILI cases and represents a quantitative, objective tool that has been well validated by both internal and external DILI experts. The RUCAM provided evidence-based results concerning liver injury by 1 drug class (antituberculotics + antiretrovirals) and 19 different drugs, comprising 900 iDILI cases. Among the top-ranking drugs were amoxicillin-clavulanate (290 cases, HLA A*02:01 or HLA A*30:02), followed by flucloxacillin (255 cases, HLA B*57:01), trimethoprim-sulfamethoxazole (86 cases, HLA B*14:01 or HLA B*14:02), methimazole (40 cases, HLA C*03:02), carbamazepine (29 cases, HLA A*31:01), and nitrofurantoin (26 cases, HLA A*33:01). In conclusion, the HLA genetics in 900 idiosyncratic drug-induced liver injury cases with evidence based on the RUCAM are available for studying the mechanistic steps leading to the injury, including metabolic factors through cytochrome P450 isoforms and processes that activate the innate immune system to the adaptive immune system.

A comprehensive analysis of liver safety across zibotentan oncology trials: knowledge of the past offers new perspectives on the present

ABSTRACT Background Endothelin receptor antagonists (ERAs) are associated with liver injury. We used data from previous oncology clinical trials to determine the liver safety profile of zibotentan, which is currently in clinical development (in combination with dapagliflozin) for chronic kidney disease and cirrhosis. Research design and methods Six global, double-blinded, phase 2b and 3 clinical trials from the zibotentan oncology development program were pooled to analyze liver safety. Descriptive statistics, proportion of liver-related adverse events, liver biochemistry parameter elevation, and shifts from baseline were analyzed, with individual case assessment. Results A total of 1532 patients received zibotentan for 285 days (mean), and 1486 patients received placebo for 320 days (mean). The frequency of any hepatic disorder preferred term was similar across zibotentan monotherapy (22/947 patients, 2.3%) and placebo monotherapy arms (30/881 patients, 3.4%). A total of 4 (0.4%) patients receiving zibotentan monotherapy experienced ALT elevations >5× ULN versus 8 (0.9%) receiving placebo. Of the seven patients receiving zibotentan who met criteria for potential Hy’s Law, there were no cases of drug-induced liver injury. Conclusions We found no evidence of zibotentan-related liver biochemistry changes among cancer-treated patients, suggesting that hepatotoxicity of ERAs is molecule-dependent, and allowing exploration of zibotentan for new indications.

Comparative histologic features among liver biopsies with biliary-pattern injury and confirmed clinical diagnoses

Biliary-pattern injury in the liver (eg, duct injury, ductular reaction, cholestasis) can occur in several conditions, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), large duct obstruction (LDO), and drug-induced liver injury (DILI). While the histologic changes in these conditions have been individually well described, distinguishing among them remains often challenging, particularly when biopsy samples are limited in size, robust clinical information is unavailable, and/or the pathologist does not feel confident in evaluating liver disease. This study evaluated histologic features that could aid the diagnosis of biliary-pattern injury on biopsy. We reviewed 121 liver biopsies from clinically confirmed cases of PBC, PSC, chronic LDO, or DILI for multiple clinical and histologic parameters. The rates of these histologic findings were then compared among different entities. Onion-skin fibrosis was seen in 14% of PSC in comparison to 0%, 5%, and 0% of PBC, DILI, and chronic LDO (P = 0.031). Florid duct lesions were identified in 21% of PBC compared to 2% of PSC and 0% of DILI and LDO (P = 0.0065). Similarly, 42% of PBC showed lobular granulomas, compared to 7% of PSC, 11% of DILI, and 33% of chronic LDO (P = 0.0001). Cholestasis was more commonly seen in DILI (42%) and chronic LDO (83%) than in PBC (4%) and PSC (16%) (P < 0.0001). Lobular chronic inflammation was found in a significantly higher percentage of PBC and LDO than of PSC and DILI (P = 0.0009). There were significantly fewer cases of PBC showing neutrophils in ductular reaction than PSC, DILI, and LDO (P = 0.0063). Histologic findings that can help suggest a diagnosis in liver biopsies with biliary-pattern injury include florid duct lesions, lobular granulomas, lack of neutrophils in ductular reaction, and lobular chronic inflammation in PBC; onion-skin fibrosis in PSC; cholestasis and feathery degeneration in DILI; and lobular granulomas, lobular chronic inflammation, cholestasis, and feathery degeneration in chronic LDO. These findings are likely most helpful when complicating factors interfere with biopsy interpretation.

Drug-induced liver injury from selective androgen receptor modulators, anabolic-androgenic steroids and bodybuilding supplements in Australia.

Reports of DILI due to herbal and dietary supplements have been increasing over time. To characterise clinical, laboratory and histopathological phenotypes and outcomes of drug-induced liver injury (DILI) due to anabolic-androgenic steroids (AAS), selective androgen receptor modulators (SARMs), and bodybuilding supplements (BBS) in Australia. Retrospective case series. Patients presented to nine Australian tertiary hospitals, 2017-2023. DILI was defined biochemically and patients were included if their treating physician attributed DILI to preceding use of AAS, SARMs or BBS. Primary endpoint was time to normalisation of liver biochemistry. Secondary endpoints were hospitalisation for investigation or management of DILI, death attributable to liver injury, and liver transplantation. Twenty-three cases of DILI were identified, involving 40 drugs: 18 AAS, 14 SARMs and eight BBS. Patients were predominantly male (22/23), with median age 30 years (IQR 26-42). Most were symptomatic (21/23). Median latency of onset was 58 days (IQR 28-112 days) from drug commencement. Most patients (17/23) were admitted to hospital. Based on updated Roussel Uclaf Causality Assessment Method, DILI was possible in 17/23, probable in 2/23 and unlikely in 4/23. Median time to normalisation of liver biochemistry was 175 days (IQR 70-292 days) from presentation. Three (3/23) were treated with corticosteroids, 14/23 were treated for itch, and one (1/23) underwent liver transplantation. There were no deaths. The prognosis of DILI from AAS, SARMs and BBS is good although liver transplantation may rarely be required. A detailed drug history is important in uncovering DILI due to these supplements.

Steroid-responsive intractable pruritus in drug-induced liver injury: a case series

Background: Drug-induced liver injury (DILI) is commonly caused by modern medications, complementary and alternative medicines (CAMs), and other toxins. DILI is an umbrella term encompassing herb-induced liver injury (HILI) caused by herbs and CAMs, in addition to other medications. Apart from the cessation of the culprit drug and the supportive management, there are no definite treatment options for DILI. Although being used in DILI, steroids are not the standard medications for DILI, except that they are indicated for a few specific conditions. Materials and Methods: We report five cases of DILI with pruritus who responded well to steroids used as rescue therapy. DILI in these five cases was caused by CAMs (1), anabolic steroids (2), dapsone (1), and antifungal drug itraconazole (1). All patients presented with jaundice and pruritus, and their conditions did not improve following the discontinuation of offending agents and the implementation of supportive care. We used the Roussel UCLAF Causality Assessment Method 2016 for causality assessment. R-value was used to describe the pattern of liver injury. All patients underwent comprehensive work-up including liver biopsy as part of the procedure to rule out other potential etiologies. Steroids were used as a last resort, and both clinical and biochemical measurements were conducted. Results: The mean age of patients was 28.8 years, and the majority of them were males (80%). The median duration from symptom onset to presentation at our hospital was 4 weeks. The mean durations for pruritus improvement and complete biochemical improvement after steroid treatment were 3.2 weeks and 11.2 weeks, respectively. Extended follow-up was done for a mean period of 29.6 weeks from symptom presentation, and none of the patients had recurrence of liver injury after discontinuation of steroids. Conclusions: Ssteroids can be used to treat as rescue therapy for severe DILI with intractable pruritus in patients with worsening liver function. Relevance for Patients: DILI in selected cases can be therapeutically managed using steroids, which, however, should not be indicated as a first-line treatment.

Selective FRET nano probe based on carbon dots and naphthalimide-isatin for the ratiometric detection of peroxynitrite in drug-induced liver injury.

Drug-induced liver injury (DILI) is the most common cause for acute liver failure in the USA and Europe. However, most of DILI cases can recover or be prevented if treatment by the offending drug is discontinued. Recent research indicates that peroxynitrite (ONOO-) can be a potential indicator to diagnose DILI at an early stage. Therefore, the establishment of an assay to detect and track ONOO- in DILI cases is urgently needed. Here, a FRET-based ratiometric nano fluorescent probe CD-N-I was developed to detect ONOO- with high selectivity and excellent sensitivity. This probe consists of carbon dots and a naphthalimide-isatin peroxynitrite sensing system assembled based on electrostatic interactions. Using CD-N-I we were able to detect exogenous ONOO- in live cells and endogenous ONOO- in APAP-induced liver injury of HepG2 cells.

Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

A pharmacovigilance study on drug-induced liver injury associated with antibody-drug conjugates (ADCs) based on the food and drug administration adverse event reporting system

ABSTRACT Background This study aimed to assess the association between drug-induced liver injury (DILI) and antibody-drug conjugates (ADCs) by comprehensively evaluating spontaneous reports submitted to the Food and Drug Administration Adverse Event Reporting System (FAERS) database from 2004Q1 to 2022Q3. Research design and Methods All DILI cases with ADCs as primary suspected drugs were extracted from the FAERS database from 2004Q1 to 2022Q3 using OpenVigil 2.1. The reporting odds ratio (ROR) and the proportional reporting ratio (PRR) for reporting the association between different drugs and DILI risk were calculated. Results A total of 504 DILI cases were attributed to ADCs during the study period. Patients with ADCs-related DILI (n = 504) had a mean age of 56.2 ± 18.4 years, with 167 cases not reporting patients’ age. Females and males comprised 42.5% and 44.0% of the cases, respectively, while there was no information on gender in 13.5% of the cases. The DILI signals were detected in trastuzumab emtansine, enfortumab vedotin, brentuximab vedotin, polatuzumab vedotin, gemtuzumab ozogamicin, inotuzumab ozogamicin, and trastuzumab deruxtecan. Conclusions The FAERS data mining suggested an association between DILI and some ADCs. Further studies are warranted to unraveling the underlying mechanisms and taking preventive measures for ADCs-related DILI.

S3421 A Rare Case of Drug-Induced Liver Injury Due to Sea Moss Consumption

S3421 A Rare Case of Drug-Induced Liver Injury Due to Sea Moss Consumption

S3695 Anamu Tea: A Rare Case of Drug-Induced Liver Injury

S3695 Anamu Tea: A Rare Case of Drug-Induced Liver Injury

Safety of Herbal Medicines on Liver Function in Functional Dyspepsia Patients: A Single-Center Retrospective Study

Objectives: This study analyzed laboratory serum data results before and after patients took herbal medicine to confirm the clinical safety of herbal medicine. In addition, in the event of liver damage, the case was analyzed to confirm the characteristics of liver damage and the possibility of liver damage caused by herbal medicine.Methods: A retrospective chart review of the effects of herbal medicine on liver function in patients diagnosed with functional dyspepsia was conducted. The electronic medical records of 128 patients in a single hospital were reviewed.Results: The statistical analysis revealed a statistically significant decrease in liver function-related laboratory serum data after taking herbal medicine (p&lt;0.05). In addition, among 128 patients, there were two cases of drug-induced liver injury (DILI) (1.56%).Conclusion: Taking herbal medicine prescribed by experts does not significantly affect liver function in patients with functional dyspepsia. Rather, the liver levels of the subjects showed a significant decrease after taking herbal medicine. To support these results, further large-scale multicenter prospective studies are necessary.

Vancomycin-Induced Liver Injury, DRESS, and HLA-A∗32:01

Intravenous vancomycin therapy can cause liver injury as well as "drug reaction with eosinophilia and systemic symptoms" (DRESS) syndrome. This study aimed to better define the clinical features and HLA associations of vancomycin-induced liver injury. To describe clinical, biochemical, and temporal characteristics of vancomycin-induced liver injury. Cases of liver injury with recent exposure to vancomycin who were enrolled in the US Drug-induced Liver Injury Network between 2004 and 2020 were assessed. Sequencing of HLA alleles was performed on stored blood samples. Among 1697 cases of drug-induced liver injury identified between 2004 and 2021, 9 (0.5%) were attributed to intravenous vancomycin. The 9 cases included 6 men, median age 60 years (range, 23-85 days), and treatment for 26 days (range, 1-34 days). The clinical presentation was DRESS syndrome in 8 patients, of whom 6 received corticosteroids. Liver injury varied from hepatocellular to cholestatic and from mild (n= 5) to fatal (n= 1). In survivors, liver injury and DRESS syndrome ultimately resolved. HLA typing demonstrated the HLA-A∗32:01 allele in 7 vancomycin cases (78%, all with DRESS syndrome), versus 1 of 81 cases (1.2%) exposed but not attributed to vancomycin, and 113 of 1708 cases (6.6%) without vancomycin exposure. The allele frequency in vancomycin cases was 0.44 compared with less than 0.04 in US populations. Vancomycin-induced liver injury is commonly associated with DRESS syndrome and linked to HLA-A∗32:01. HLA-A∗32:01 testing could be considered early to risk-stratify patients using long-term intravenous vancomycin therapy.

Combination vardenifil and tadalifil drug induced liver injury; case report and review of the literature of liver injury associated with phosphodiesterase type 5 inhibitors.

Phosphodiesterase type 5 inhibitors (PDE5I) are prescribed for erectile dysfunction and pulmonary hypertension. Despite its widespread use, there are only seven cases of drug-induced liver injury (DILI) associated with PDE5I, none associated with vardenafil or avanafil. We report a patient who had taken vardenafil and tadalafil individually for several years without developing symptoms of liver injury. However, after taking vardenafil and tadalafil together on 2 consecutive days, he developed severe cholestasis. Causality was determined using Roussel Uclaf causality assessment method (RUCAM). The patient is a 72-year-old White man in excellent health who drank 2 units of alcohol, three times/week. Previously, he had used vardenafil for more than 2 years and tadalafil for 3 months as single agent for erectile dysfunction without any complications. He took vardenafil and tadalafil for 2 consecutive days and 5 days later, he developed dyspepsia, loss of appetite, jaundice, and intense itching. Liver tests showed mixed cholestatic/hepatocellular pattern of injury. Histology showed marked cholestasis with minimal inflammation. He remained cholestatic for 5 weeks before a full recovery 2 months later. The patient then resumed vardenafil monotherapy with no recurrent liver dysfunction. RUCAM causality score 7 indicates that the combination of PDE5I is probable cause of liver injury. The similarities among the eight cases of PDE5I DILI include a relatively short latency, cholestatic histological features, and complete recovery. Biochemical pattern of liver injury is variable. PDE5I DILI is a rare event that can result in severe acute liver injury.

Capmatinib-Induced Liver Injury as Emerging Toxicity of MET Inhibitors in Patients With NSCLC Pretreated With Immune Checkpoint Inhibitors

Safety data on MET inhibitors in patients with advanced NSCLC harboring MET exon 14 mutation and treated with frontline immune checkpoint inhibitors (ICIs) are still limited. Here, we describe clinical characteristics, liver biopsy features, and management of liver injury of two patients with a diagnosis of MET exon 14-mutant NSCLC receiving capmatinib after ICI failure. On the basis of histologic findings and exclusion of other potential causes, a diagnosis of drug-induced liver injury (DILI) associated with portal fibrosis was made in both cases. The use of hepatoprotective drugs, in addition to oral ursodeoxycholic acid, resulted in liver blood tests normalization. To provide a global safety perspective, we queried the Food and Drug Administration Adverse Event Reporting System and detected a robust disproportionality signal. Out of the 918 total reports with capmatinib from the Food and Drug Administration Adverse Event Reporting System database, DILI was recorded in 43 cases (4.7%), mostly serious (93.0%) with hospitalization and death recorded in 25.6% and 16.3% of the cases, respectively. The median time to onset was 42 days, with discontinuation and positive dechallenge documented in 41.9% and 39.5% of the cases, respectively. Anti–programmed cell death protein-1 agents were coreported in 11 DILI cases. Only two cases of DILI out of 105 reports were found for tepotinib. Our data support a potential association between capmatinib and DILI in patients who have also been previously exposed to immunotherapy. Considering the potential implications for sequence strategy and timing of ICI and MET inhibitor, further investigation is warranted.

HLA-B*53:01 Is a Significant Risk Factor of Liver Injury due to Phenytoin and Other Antiepileptic Drugs in African Americans.

To investigate human leukocyte antigen alleles associated with liver injury due to antiepileptic drugs (AEDs) in African Americans (AA). In this study, 21 AA with AED drug-induced liver injury (DILI), 176 AA with DILI due to non-AEDs, and 5816 AA population controls were included. HLA-B*53:01 was significantly associated with aromatic AED-DILI (odds ratio: 4.52, 95% confidence interval: 2.42-8.44, P = 1.46 × 10 -5 ). Phenytoin DILI showed the strongest association with HLA-B*53:01 (odds ratio: 9.17; 95% confidence interval: 3.61-23.28, P = 1.1 × 10 -5 ). The HLA-B*53:01 allele was carried by 8 of 9 AA phenytoin DILI cases. HLA-B*53:01 is a significant risk factor of liver injury due to antiepileptics, particularly phenytoin, in AA.