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Feeding male Collaborative Cross mice an obesogenic diet allows modeling NAFLD at the population level. The development of NAFLD coincided with significant hepatic transcriptomic changes in this model. Genes (724) were differentially expressed and expression of 68 genes strongly correlated with the extent of hepatic lipid accumulation. Partial least squares modeling showed that derived hepatic gene expression signatures may help to identify individual mouse strains that are highly susceptible to the development of NAFLD.

BACKGROUND AND AIMS Reports of moderate to severe liver injury associated with tocilizumab, an interleukin-6 (IL-6) receptor antagonist, have been reported in the post-marketing setting. This case series aims to characterize cases of tocilizumab-associated clinically significant hepatic injury. METHODS We analysed cases of severe acute liver injury associated with tocilizumab reported in the FDA Adverse Event Reporting System and the medical literature. RESULTS We identified 12 cases in which tocilizumab was a suspected primary cause of liver injury and eight cases in which serious sequelae of underlying or coincident viral hepatitis were temporally associated with its use. Using the Drug-Induced Liver Injury Network (DILIN) severity scale, five of 12 cases were Grade 5 (two liver transplants, three deaths), one was Grade 4 (liver failure) and six were Grade 3 (serious events with elevated bilirubin). Two cases reported liver atrophy with low hepatocellular expression of Ki-67, a marker of cellular proliferation. Among the eight cases of tocilizumab-associated viral hepatitis exacerbation, three were scored as DILIN severity Grade 5 (one liver transplant, two deaths), one was Grade 4 (liver failure), and four were Grade 3. The reported viral hepatitis events were hepatitis B virus (HBV) reactivation (n = 3), hepatitis C virus (HCV) flare (n = 1), cytomegalovirus (CMV)-induced liver failure (n = 1), Epstein-Barr virus hepatitis (n = 1), acute hepatitis E (HEV, n = 1) and HEV-induced macrophage activation syndrome (n = 1). CONCLUSION Tocilizumab may be a primary cause of severe liver injury, as well as exacerbate underlying viral hepatitis. The disruption by tocilizumab of IL-6-mediated immune protection and hepatocyte regeneration may aggravate clinical outcomes in some cases.

Ulipristal acetate (ulipristal) is a selective progesterone receptor modulator that has been marketed for daily use in Europe and Canada to reduce symptoms caused by uterine fibroids. Long-term use of some other members of this class of 19-norprogesterone-derived agents has been associated with idiosyncratic hepatotoxicity. We analyzed postmarketing reports of suspected drug-induced liver injury associated with the daily use of 5 mg of ulipristal to treat symptoms of uterine fibroids. We searched for reports of serious liver injury associated with ulipristal, submitted to the US Food and Drug Administration through 31 January, 2020. Cases of liver injury temporally associated with long-term ulipristal exposure that reported combined increases of serum aminotransferases and bilirubin were individually assessed using a five-tier categorical scale of likelihood for a causal association with the drug by individuals with expertise in drug-induced liver injury evaluation. Individual cases that did not culminate in liver failure, death, or liver transplantation were also assessed for their causal association with ulipristal by the Roussel Uclaf Causality Assessment Method. We identified nine non-US cases that met the criteria for inclusion in our search for cases of serious liver injury associated with ulipristal. Five cases reported clinical outcomes of liver transplantation and/or death and all were assessed to have a probable causal association with ulipristal acetate. Evaluation of the other four cases reporting resolution of liver injury after treatment discontinuation revealed a possible or probable causal relationship with ulipristal. We identified postmarketing cases of serious acute drug-induced liver injury causally associated with ulipristal used to treat uterine fibroids, some with outcomes of liver transplant and/or death. The presence of common structural features identified with certain selective progesterone receptor modulators in the treatment of chronic conditions may indicate a liability for idiosyncratic drug-induced liver injury.

Interindividual variability and sexual dimorphisms in the development of nonalcoholic fatty liver disease (NAFLD) are still poorly understood. In the present study, male and female strains of Collaborative Cross (CC) mice were fed a high-fat and high-sucrose (HF/HS) diet or a control diet for 12 weeks to investigate interindividual- and sex-specific variations in the development of NAFLD. The severity of liver steatosis varied between sexes and individual strains and was accompanied by an elevation of serum markers of insulin resistance, including increases in total cholesterol, low-density lipoproteins, high-density lipoproteins, phospholipids, and glucose. The development of NAFLD was associated with overexpression of the critical fatty acid uptake and de novo lipogenesis genes Pparg, Mogat1, Cd36, Acaab1, Fabp2, and Gdf15 in male and female mice. The expression of Pparg, Mogat1, and Cd36 was positively correlated with liver triglycerides in male mice, and Mogat1 and Cd36 expression were positively correlated with liver triglycerides in female mice. Our results indicate the value of CC mice in combination with HF/HS diet-induced alterations as an approach to study the susceptibility and interindividual variabilities in the pathogenesis of nonalcoholic fatty liver and early nonalcoholic steatohepatitis at the population level, uncovering of susceptible and resistant cohorts, and identifying sex-specific molecular determinants of disease susceptibility.

Non-alcoholic fatty liver disease (NAFLD), one of the most common forms of chronic liver disease, is characterized by the excessive accumulation of lipid species in hepatocytes. Recent studies have indicated that in addition to the total lipid quantities, changes in lipid composition are a determining factor in hepatic lipotoxicity. Using ultra-high performance liquid chromatography coupled with electrospray tandem mass spectrometry, we analyzed the esterified fatty acid composition in 24 strains of male and female Collaborative Cross (CC) mice fed a high fat/high sucrose (HF/HS) diet for 12 weeks. Changes in lipid composition were found in all strains after the HF/HS diet, most notably characterized by increases in monounsaturated fatty acids (MUFA) and decreases in polyunsaturated fatty acids (PUFA). Similar changes in MUFA and PUFA were observed in a choline- and folate-deficient (CFD) mouse model of NAFLD, as well as in hepatocytes treated in vitro with free fatty acids. Analysis of fatty acid composition revealed that alterations were accompanied by an increase in the estimated activity of MUFA generating SCD1 enzyme and an estimated decrease in the activity of PUFA generating FADS1 and FADS2 enzymes. PUFA/MUFA ratios were inversely correlated with lipid accumulation in male and female CC mice fed the HF/HS diet and with morphological markers of hepatic injury in CFD diet-fed mouse model of NAFLD. These results demonstrate that different models of NAFLD are characterized by similar changes in the esterified fatty acid composition and that alterations in PUFA/MUFA ratios may serve as a diagnostic marker for NAFLD severity.

Immune checkpoint inhibitors (ICIs) represent a promising therapy for many types of cancer. However, only a portion of patients respond to this therapy and some patients develop clinically significant immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI), an immune-related adverse event (irAE) that may require the interruption or termination of treatment and administration of systemic corticosteroids or other immunosuppressive agents. Although the incidence of ILICI is lower with monotherapy, the surge in combining ICIs with chemotherapy, targeted therapy, and combination of different ICIs has led to an increase in the incidence and severity of ILICI - a major challenge for development of effective and safe ICI therapy. In this review, we highlight the importance and contribution of the liver microenvironment to ILICI by focusing on the emerging roles of resident liver cells in modulating immune homeostasis and hepatocyte regeneration, two important decisive factors that dictate the initiation, progression, and recovery from ILICI. Based on the proposed contribution of the liver microenvironment on ICILI, we discuss the clinical characteristics of ILICI in patients with preexisting liver diseases, as well as the challenges of identifying prognostic biomarkers to guide the clinical management of severe ILICI. A better understanding of the liver microenvironment may lead to novel strategies and identification of novel biomarkers for effective management of ILICI.

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 treatment options after DILI is diagnosed are needed. Qualification efforts have been hindered by lack of properly stored and consented biospecimens that are linked to clinical data relevant to a specific context of use. Recommendations are made for biospecimen collection procedures, with the focus on clinical trials, and for specific emerging biomarkers to focus qualification efforts.

Background The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials. Aims This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH. Methods This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic. Results Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules. Conclusions This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH.

Immune checkpoint inhibitors (ICIs) represent a promising therapy for many types of cancer. However, only a portion of patients respond to this therapy and some patients develop clinically significant immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI), an immune-related adverse event (irAE) that may require the interruption or termination of treatment and administration of systemic corticosteroids or other immunosuppressive agents. Although the incidence of ILICI is lower with monotherapy, the surge in combining ICIs with chemotherapy, targeted therapy, and combination of different ICIs has led to an increase in the incidence and severity of ILICI - a major challenge for development of effective and safe ICI therapy. In this review, we highlight the importance and contribution of the liver microenvironment to ILICI by focusing on the emerging roles of resident liver cells in modulating immune homeostasis and hepatocyte regeneration, two important decisive factors that dictate the initiation, progression, and recovery from ILICI. Based on the proposed contribution of the liver microenvironment on ICILI, we discuss the clinical characteristics of ILICI in patients with preexisting liver diseases, as well as the challenges of identifying prognostic biomarkers to guide the clinical management of severe ILICI. A better understanding of the liver microenvironment may lead to novel strategies and identification of novel biomarkers for effective management of ILICI.

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events. Electronic supplementary material The online version of this article (10.1007/s40264-020-01014-2) contains supplementary material, which is available to authorized users.

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.

Immune checkpoint inhibitors (ICIs) block CTLA-4, PD-1 and PD-L1, or other molecules that control antitumour activities of lymphocytes. These products are associated with a broad array of immune-related toxicities affecting a variety of organs, including the liver. ICI-associated immune-mediated hepatitis (IMH) ranges in severity between mild and life-threatening and is marked by findings that bear both similarities as well as differences with idiopathic autoimmune hepatitis. Hepatotoxic events are often detected in clinical trials of ICIs that are powered for efficacy. Risk levels for ICI-induced liver injury may be impacted by the specific checkpoint molecule targeted for treatment, the ICI dose levels, and the presence of a pre-existing autoimmune diathesis, chronic infection or tumour cells which infiltrate the liver parenchyma. When patients develop liver injury during ICI treatment, a prompt assessment of the cause of injury, in conjunction with the application of measures to optimally manage the adverse event, should be made. Strategies to manage the risk of IMH include the performance of pretreatment liver tests with regular monitoring during and after ICI treatment and patient education. Using Common Terminology Criteria for Adverse Events developed at the National Cancer Institute to measure the severity level of liver injury, recommended actions may include continued ICI treatment with close patient monitoring, ICI treatment suspension or discontinuation and/or administration of corticosteroids or, when necessary, a non-steroidal immunosuppressive agent. The elucidation of reliable predictors of tumour-specific ICI treatment responses, as well as an increased susceptibility for clinically serious immune-related adverse events, would help optimize treatment decisions for individual patients.

With the rise in polypharmacy, it is increasingly important to identify drug–drug interactions (DDIs) that cause serious adverse events in a timely manner. The purpose of the study was to investigate the utility of systematic data mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for interactions between statins (HMG-CoA reductase inhibitors) and other drugs that underlie a higher risk for rhabdomyolysis. The strength of association for the reporting of rhabdomyolysis with each statin–drug combination was measured using Bayesian data mining scores, the Interaction Signal Score (INTSS), and simple proportions that were calculated as the reporting odds ratio (ROR). Scores >1.0 indicate disproportionately higher than expected reporting. A manual case review highlighted strengths and limitations of these measures. As expected, clarithromycin and cyclosporine produced high measures of disproportionate reporting of rhabdomyolysis with lovastatin and simvastatin. Drugs with no known predilection to contribute to statin myopathy produced scores

Two overarching goals tied to a futuristic vision of personalized medicine are to maximize individually derived benefits from available therapeutic drugs or biological agents and identify a reliable set of predictors of toxic outcomes to optimally manage a patient’s treatment-related risk. This article will primarily address the second of these goals with a specific focus on challenges faced in the development of pharmacogenomic markers that would be used by practitioners to predict individual susceptibility to serious adverse drug reactions. The potential complexity of polygenic modifiers of risk for certain adverse drug reactions and demographic diversity in the prevalence of genomic variants pose significant challenges in the development of useful predictive biomarkers. Implementing rigorous scientific and logistical strategies to address these will be crucial in order to achieve meaningful success.

Background: In pre-approval trials, there was an increased incidence of mild, transient elevations of liver aminotransferases in study subjects treated with dimethyl fumarate (DMF). Objective/methods: To evaluate post-marketing cases of drug-induced liver injury associated with DMF. Results: We identified 14 post-marketing cases of clinically significant liver injury. Findings included newly elevated serum liver aminotransferase and bilirubin levels that developed as early as a few days after the first dose of DMF. The pattern of liver injury was primarily hepatocellular. No cases resulted in liver failure. Conclusion: Health professionals should be alerted to possible serious liver injury in patients receiving DMF.

Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is one of the most devastating of adverse drug reactions (ADRs) and was, until recently, essentially unpredictable. With the discovery of several risk alleles for drug-induced SJS/TEN and the demonstration of effectiveness of screening in reducing incidence, the stage is set for implementation of preventive strategies in populations at risk. Yet much remains to be learned about this potentially fatal complication of commonly used drugs.

Importance Toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS) are rare, acute, life-threatening dermatologic disorders involving the skin and mucous membranes. Research into these conditions is hampered by a lack of standardization of case reporting and data collection. Objective To establish a standardized case report form to facilitate comparisons and maintain data quality based on an international panel of SJS/TEN experts who performed a Delphi consensus-building exercise. Evidence Review The elements presented for committee scrutiny were adapted from previous case report forms and from PubMed literature searches of highly cited manuscripts pertaining to SJS/TEN. The expert opinions and experience of the members of the consensus group were included in the discussion. Findings Overall, 21 out of 29 experts who were invited to participate in the online Delphi exercise agreed to participate. Surveys at each stage were administered via an online survery software tool. For the first 2 Delphi rounds, results were analyzed using the Interpercentile Range Adjusted for Symmetry method and statements that passed consensus formulated a new case report form. For the third Delphi round, the case report form was presented to the committee, who agreed that it was “appropriate and useful” for documenting cases of SJS/TEN, making it more reliable and valuable for future research endeavors. Conclusions and Relevance With the consensus of international experts, a case report form for SJS/TEN has been created to help standardize the collection of patient information in future studies and the documentation of individual cases.

The assessment of risk for serious, life-threatening drug-induced liver injury (DILI) associated with a suspect drug, biological agent, or herbal product depends on an iterative analysis of pre- and postmarket datastreams. Because serious cases of idiosyncratic DILI are typically rare, regulatory scientists seek strategies that accurately predict from clinical trial data which study drugs will be likely to cause these events in a large postmarket treatment population, e.g., through the identification of cases that are consistent with Hy's law. This objective is only achievable if rigorous standards in study subject monitoring, data collection and analysis of liver injury cases for causality are followed. In the future, the development of more effective predictive and analytic tools in preclinical and clinical testing will provide a framework to reliably identify new agents that have hepatotoxic profiles as well as those individuals who are susceptible to develop serious DILI.

Purpose The validity of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify diagnoses of severe acute liver injury (SALI) is not well known. We examined the positive predictive values (PPVs) of hospital ICD-9-CM diagnoses in identifying SALI among health plan members in the Mini-Sentinel Distributed Database (MSDD) for patients without liver/biliary disease and for those with chronic liver disease (CLD).

In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized.

Objective: The purpose of this case series is to characterize a recently identified association of the antiepileptic drug (AED) lamotrigine with aseptic meningitis based on cases reported to the Food and Drug Administration (FDA)9s Adverse Event Reporting System (AERS) database. Methods: We performed a data mining analysis of 9 AEDs from the FDA9s AERS database. We applied the multi-item gamma Poisson shrinker (MGPS) algorithm to the entire AERS database through November 2, 2009, to generate empirical Bayes geometric mean (EBGM) values with corresponding confidence intervals for 9 AEDs and the adverse event code “meningitis aseptic.” The AERS database was also searched for postmarketing reports of aseptic meningitis associated with lamotrigine and a detailed review of each case was performed. Results: Forty AERS cases were identified in this review. Findings from the AERS reports revealed CSF profiles with features of both bacterial as well as viral meningitis. Fifteen cases documented a positive rechallenge; the median time to onset of symptoms upon rechallenge was only 60 minutes. Data mining analysis of several anticonvulsants resulted in disproportionate reporting solely for lamotrigine. Conclusion: There appears to be an association between lamotrigine use and aseptic meningitis. It is notable that nearly 40% of cases in this case series reported a positive rechallenge. Lamotrigine-associated aseptic meningitis should be considered in the differential diagnosis of culture-negative meningitis. This case series highlights the need for continued pharmacovigilance and the importance of systematic monitoring of patients treated with antiepileptic medications.

Drug-induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH).

Joseph M. Betz, PhD Linda Anderson, PhD Mark I. Avigan, MD Joanne Barnes, PhD Norman R. Farnsworth, PhD Barbro Gerden, MD Leigh Henderson, MS Edward J. Kennelly, PhD Uwe Koetter, PhD Stephanie Lessard, MS Tieraona Low Dog, MD, PhD Michelle McLaughlin, BS Belal Naser, MD Ruediger G. W. Osmers, MD, PhD Linda S. Pellicore, PhD John R. Senior, PhD Richard B. van Breemen, PhD Wolfgang Wuttke, MD John H. Cardellina II, PhD

To assess spontaneous reports of rhabdomyolysis associated with simvastatin (SV) and pravastatin (PV) for evidence of CYP3A4 interaction. Clinical trial results advocate cholesterol lowering in high-risk patients including diabetics and the elderly. Given the association between advancing age, metabolic, and cardiovascular disease, many patients are treated with concomitant medications upon statin initiation. Although statins are generally safe, minor and severe adverse reactions arise, especially when given to patients taking concomitant medications that inhibit the statin clearance and lead to increased statin plasma concentration.We conducted a comparative case series of rhabdomyolysis reports associated with SV and PV. Domestic spontaneous reports were obtained from the FDA's Adverse Event Reporting System (AERS). Drug utilization data were obtained from IMS HEALTH and the National Ambulatory Medical Care Survey (NAMCS). Adverse event reporting rates (AER) and ratios (AERR) of rhabdomyolysis associated with SV and PV-with and without stratification by CYP3A4 inhibitor concomitancy were determined.Stratification by CYP3A4 inhibitor concomitancy did not change the rhabdomyolysis AER for PV with or without a CYP3A4 inhibitor (2.4 cases and 3.1 cases per 10 million Rx, respectively). However, stratification of SV reports with or without a concomitant CYP3A4 inhibitor resulted in a rhabdomyolysis AER (38.4 and 6.0 cases per 10 million Rx, respectively). The corresponding AERR with or without a CYP3A4 inhibitor were 0.77 for PV and 6.43 for SV.Spontaneous adverse event reports provide evidence of increased risk for rhabdomyolysis based on interaction between SV and selected CYP3A4 inhibitors.

SUMMARY Background We detected disproportionate reporting of amyotrophic lateral sclerosis (ALS) with HMG-CoA-reductase inhibitors (statins) in the Food and Drug Administration’s (FDA) spontaneous adverse event (AE) reporting system (AERS). Purpose To describe the original ALS signal and to provide additional context for interpreting the signal by conducting retrospective analyses of data from long-term, placebo-controlled clinical trials of statins. Methods The ALS signal was detected using the multi-item gamma Poisson shrinker (MGPS) algorithm. All AERS cases of ALS reported in association with use of a statin were individually reviewed by two FDA neurologists. Manufacturers of lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, and rosuvastatin were requested to provide the number of cases of ALS diagnosed during all of their placebo-controlled statin trials that were at least 6 months in duration. Results There were 91 US and foreign reports of ALS with statins in AERS. The data mining signal scores for ALS and statins ranged from 8.5 to 1.6. Data were obtained from 41 statin clinical trials ranging in duration from 6 months to 5 years and representing approximately 200 000 patient–years of exposure to statin and approximately 200 000 patient–years of exposure to placebo. Nine cases of ALS were reported in statin-treated patients and 10 cases in placebo-treated patients. Conclusions Although we observed a data mining signal for ALS with statins in FDA’s AERS, retrospective analyses of 41 statin clinical trials did not reveal an increased incidence of ALS in subjects treated with a statin compared with placebo. Copyright # 2008 John Wiley & Sons, Ltd.

The safety profile of newly approved drugs and therapeutic biologics is less well developed by pre-marketing clinical testing than is the efficacy profile. The full safety profile of an approved product is established during years of clinical use. For nearly 40 years, the FDA has relied on the voluntary reporting of adverse events by healthcare practitioners and patients to help establish the safety of marketed products. Epidemiologic studies, including case series, secular trends, case-control and cohort studies, are used to supplement the investigation of a safety signal. Ideally, active surveillance systems would supplement the identification and exploration of safety signals. The FDA has implemented a number of initiatives to help identify safety problems with drugs and continues to evaluate their efforts.

Published literature suggests that attention-deficit/hyperactivity disorder (ADHD) affects 4% of adults and that as many as 60% of children with a diagnosis of ADHD will continue to have problems with inattention and impulsivity in adulthood. We analyzed cross-sectional prescription claims data and data from a national survey of office-based physicians for further inference on the likelihood of treatment with ADHD medications into adulthood.This study used data from a proprietary, national survey of office-based physicians (the IMS Health National Disease and Therapeutic Index, NDTI) to describe the indication associated with office visits with mention of common stimulant medications and atomoxetine. Enrollment and prescription claims data maintained by a large national health-care company were analyzed for age-specific utilization of these same agents.Data from the NDTI suggest that the vast majority of visits associated with a stimulant medication or atomoxetine was coded with a diagnosis consistent with a mental health condition and not obesity/weight loss. The health plans included in this study processed 222,096 prescriptions for stimulant medications and atomoxetine among 43,175 unique patients aged 1-64 years during the calendar year 2004. Analyses of pharmacy claims data showed a steep increase in use through age 11 (prevalence=70.3 per 1,000 covered lives) followed by a marked decrease and plateau from age 25 through age 64 years (prevalence=5 to 10 per 1,000 covered lives).On the basis of comparison of the prevalence rate peak of 70 per 1,000 around age 11 years to a plateau of 7 per 1,000 during the early career years, our results are consistent with a prediction that at least one child in 10 placed on an ADHD medication in childhood will receive treatment in to adulthood. The decrease in the prevalence of use of these medications with advancing age as seen in this cross-sectional study may reflect upon several clinical and secular factors.

Registrational studies of patients treated with tegaserod for irritable bowel syndrome (IBS) suggest an increased risk for cholecystectomy versus treatment with placebo.To study cholecystectomy rates in association with tegaserod within a large administrative medical claims database.Patients were drawn from a large population within the US with commercial medical insurance. The primary analysis consisted of a comparison of the observed incidence rate for cholecystectomy claims among a large cohort of new-to-therapy tegaserod users with an incidence rate published for tegaserod-naive patients classified with IBS within the same insured population.An inception cohort of 7475 individuals with up to 103 weeks of claims history following initiation of therapy with tegaserod was identified. After a follow-up of 3 months (and thus similar to the longest registrational trials), the observed cholecystectomy incidence rate was 340 per 10,000 person-years (95% CI 258, 442). The rate of cholecystectomy was highest in the earliest months of observation following initiation of tegaserod. The observed cholecystecomy incidence rate is 2.9 times higher than an IBS-specific rate of 119 per 10,000 person-years as published for patients so classified within the same insured population.Based on a large, inception cohort, we report a strong temporal association between the initiation of tegaserod therapy and an increased rate for cholecystectomy. The effect size at 3 months was similar to the relative risk for cholecystectomy reported in registrational studies comparing tegaserod with placebo. As misclassification of initial diagnosis for patients presenting with biliary colic-like symptoms may occur, precise measurements of tegaserod-related relative risk for cholecystectomy from observational studies are problematic and will require prospective studies.

Drugs such as alosetron that modulate serotonin effects by stimulating or blocking its receptors may play an important role in the treatment of some patients with irritable bowel system. In the case of alosetron, a 5HT-3 antagonist, an analysis of data from randomized clinical trials and postmarketing experiences have demonstrated a causal relationship between this drug and ischemic colitis and serious complications of constipation. Because the mechanism(s) of drug-induced ischemic colitis and possibly other forms of intestinal ischemia associated with alosetron have not been elucidated, there is need to further assess risk with regard to patient susceptibility and other factors.

Hepatosplenic T cell lymphoma (HSTCL) are rare cancers ( approximately 100 published cases worldwide) and comprise 5% of peripheral T cell lymphomas. As of October 5, 2006, the FDA's Adverse Event Reporting System has received 8 cases of HSTCL in young patients using infliximab, a tumor necrosis factor-alpha blocking agent, to treat inflammatory bowel disease (6 of the 8 cases had a fatal outcome). All 8 patients were receiving concomitant immunosuppressant therapy (eg, azathioprine, prednisone). It has not been established that infliximab had an exclusive or primary role in the pathogenesis of these HSTCL cases; however, it appears that patients using this product may be at greater risk for developing this rare lymphoma.

A workshop sponsored by the Human Toxicology Project Consortium (HTPC), "Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action" brought together experts from a wide range of perspectives to inform the process of pathway development and to advance two prototype pathways initially developed by the European Commission Joint Research Center (JRC): liver-specific fibrosis and steatosis. The first half of the workshop focused on the theory and practice of pathway development; the second on liver disease and the two prototype pathways. Participants agreed pathway development is extremely useful for organizing information and found that focusing the theoretical discussion on a specific AOP is extremely helpful. In addition, it is important to include several perspectives during pathway development, including information specialists, pathologists, human health and environmental risk assessors, and chemical and product manufacturers, to ensure the biology is well captured and end use is considered.

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 to achieve this goal the systematic acquisition of protocol-specified clinical measures and lab specimens from all study subjects is crucial. In addition, standard DILI terms that address the diverse clinical and pathologic signatures of DILI were considered essential. There was a strong consensus that clinical and lab analyses necessary for the evaluation of cases of acute liver injury should be consistent with the US Food and Drug Administration (FDA) guidance on pre-marketing risk assessment of DILI in clinical trials issued in 2009. A recommendation that liver injury case review and management be guided by clinicians with hepatologic expertise was made. Of note, there was agreement that emerging DILI signals should prompt the systematic collection of candidate pharmacogenomic, proteomic and/or metabonomic biomarkers from all study subjects. The use of emerging standardized clinical terminology, CRFs and graphic tools for data review to enable harmonization across clinical trials was strongly encouraged. Many of the recommendations made in the breakout session are in alignment with those made in the other parallel sessions on methodology to assess clinical liver safety data, causality assessment for suspected DILI, and liver safety assessment in special populations (hepatitis B, C, and oncology trials). Nonetheless, a few outstanding issues remain for future consideration.

Background: Currently, there are no satisfactory systems for defining, classifying, and/or scoring endoscopic complications, although it would be important for quality assurance, comparative studies, and outcomes research. Recently the term "negative outcomes" was proposed rather than "complications," and an approach that incorporates "measures of importance" was added to compare negative outcomes. Methods: A system was developed that defines, classifies, and grades negative outcomes with a scoring system based on measures of importance. Information was recorded on a Morbidity and Mortality (M & M) form, which was used at a monthly quality assurance (M & M) conference. Several measures of importance related to the immediate negative outcome (O) were quantified (effect of the complication on completion of the endoscopy, change in level of care, change in number of hospital days, necessity for new invasive procedures). The disability (D), defined as a residual or chronic negative outcome caused by the complication, was characterized and scored. Death (D) was also characterized, the value varying with circumstances. As a quantitative measure, an overall ODD score was used. Results: One hundred twenty-three negative outcomes were retrospectively classified using the new M & M form and the ODD score was applied for 117 complications. Complications were ranked according to the ODD score. Conclusion: A system for defining, classifying, and grading negative outcomes of endoscopic procedures is proposed with a quantitative scoring system that emphasizes measures of importance. The ODD score looks at the immediate negative outcome and also the separate long-term issues of disability and death. (Gastrointest Endosc 1997;45:128-33.)

Early prediction and accurate characterization of risk for serious liver injury associated with newly marketed drugs remains an important challenge for clinicians, the pharmaceutical industry, and regulators. To date, a biomarker that specifically indicates exposure to a drug as the etiologic cause of liver injury has not been identified. Using cumulative proportional reporting ratios (PRRs), we investigated ‘real-time’ profiles of a set of pharmaceuticals, over the first 3 years of US marketing, for the signaling of clinically serious drug-induced liver injury (DILI) in a large spontaneous-reporting database. Using report counts of hepatic failure or clinically serious liver injury obtained from the FDA Adverse Events Reporting System (FAERS) database, PRRs of adverse drug event terms were calculated by division of counts of domestic reports of these events by counts of all serious adverse events for each of 13 selected drugs associated with a broad range of hepatotoxic risk (including three linked to only rare instances of clinically apparent liver injury) with reference to all other drugs in the database. Drug-specific cumulative PRRs were measured at successive intervals (calendar quarters) using cumulative tallies of FAERS reports to generate time-based profiles over the initial 3 years of US marketing. In the set of drugs analyzed, those with no known hepatotoxic risk demonstrated time-based cumulative PRR profiles that approximate the background rates of hepatic failure and serious liver injury reported in the entire FAERS database. In contrast, those that were removed from marketing or subjected to marketing restrictions due to their potential to cause liver injury were associated with profiles of rapidly rising cumulative PRRs that were greater than 5 within the first 10 million domestic prescriptions or the first four quarters of US marketing. The systematic tracking and identification of rising PRRs for DILI associated with newly marketed pharmaceutical and biological agents is a valuable tool for identification of safety signals within the FAERS database. Disproportionality profiling of spontaneous reports in FAERS (e.g., cumulative PRR measurements), which signals an association between a recently marketed drug and liver injury, is not a method to quantitatively measure drug-related risk. Regulatory actions in response to emerging drug safety concerns often depend on an accurate assessment of risks using multiple sources of data and the consideration of overall benefits and risks of the agent. Causality must be determined through analysis of individual cases to exclude other etiologies of liver injury. The FAERS database can be used to advance empiric hepatotoxicity time-trending reporting levels for newly marketed agents in order to rapidly identify recently launched potential hepatotoxic agents and initiate further evaluation.

The efficient identification and characterization of risk for clinically serious drug-induced liver injury (DILI) associated with newly developed pharmaceuticals and biological agents are important objectives for regulatory science. In the United States, the implementation of consistent analytic and risk management approaches with a recently expanded set of regulatory tools is expected to have a positive public health benefit. Cellular and molecular mechanisms that underlie DILI must be more fully elucidated in order to develop reliable biomarkers that will accurately predict which new drugs are destined to cause clinically serious DILI, identify those patients who are at increased risk, or forecast progression from mild to serious organ injury. Both consistent monitoring practices and comprehensive clinical evaluation of patients with liver injury during clinical trials are required to estimate DILI risk in a large treatment population. Moreover, thorough analyses of idiosyncratic DILI cases in spontaneous reports and postmarketing clinical studies play a critical role in risk assessment. Finally, optimal product labeling, as well as effective risk communication and management, should reflect cumulative risk-related data and overall product-associated benefit and risk considerations.

Hepatocyte growth factor/scatter factor (HGF/SF) is a protein growth factor whose pleiotropic effects on epithelial cells include the stimulation of motility, mitosis and tubulogenesis. These responses are mediated by the cell surface tyrosine kinase receptor c-met. Because both the cytokine and receptor are found in the gastrointestinal tract, we have studied the effects of HGF/SF on transformed gut epithelial cells which express c-met. Here we describe the response of a new transformed human jejunal epithelioid cell line (HIE-7) to HGF/SF. Morphologically HIE-7 cells are immature. Their epithelial lineage was confirmed by reactivity with the epithelial specific antibodies AE1/AE3, Cam 5.2, Ber-EP4 and anti-EMA and is consistent with their expression of c-met mRNA and protein. In addition, electron microscopic analysis revealed the presence of primitive junctions and rudimentary microvilli, but features of polarization were absent. When grown on reconstituted basement membranes, HIE-7 cells formed closely associated multicellular cord-like structures adjacent to acellular spaces. However, the cells did not mature structurally, form lumen-like structures or express disaccharidase mRNA, even in the presence of recombinant HGF (rHGF). On the other hand, rHGF induced HIE-7 cells to scatter and stimulated their rapid migration in a modified wound assay. To determine whether the mitogenic effect caused by rHGF is associated with HIE-7 cell invasiveness across reconstituted basement membranes, a Boyden chamber chemoinvasion assay was performed. rHGF stimulated a 10-fold increase in the number of HIE-7 cells that crossed the basement membrane barrier, while only stimulating a small increase in chemotaxis across a collagen IV matrix, suggesting that the cytokine activates matrix penetration by these cells. rHGF also stimulated the invasion of basement membranes by an undifferentiated rat intestinal cell line (IEC-6) and by two human colon cancer cell lines which are poorly differentiated (DLD-1 and SW 948). In contrast, two moderately well differentiated colon cancer cell lines (Caco-2 and HT-29) did not manifest an invasive response when exposed to rHGF. These results suggest that HGF/SF may play a significant role in the invasive behavior of anaplastic and poorly differentiated gut epithelial tumors.

Background Progressive multifocal leukoencephalopathy (PML), a rare, potentially fatal demyelinating disease, affects primarily immunocompromised individuals. The Food and Drug Administration (FDA) received reports of PML associated with efalizumab (Raptiva), a biologic agent approved for psoriasis. In July 2009, efalizumab was voluntarily withdrawn from the US market because of the risk of PML. Objective To describe 3 cases of PML in psoriasis patients treated with efalizumab. Methods The FDA's Adverse Event Reporting System (AERS) database was searched for post-marketing reports of PML associated with biologic agents that are FDA approved for psoriasis (adalimumab, alefacept, efalizumab, etanercept, infliximab) from market approval to January 30, 2009. Results Twelve cases suggestive of PML were identified: adalimumab (1), efalizumab (4), etanercept (3), and infliximab (4). Efalizumab was the only drug with cases reporting PML in the setting of psoriasis. All cases of PML in efalizumab-treated patients presented 3 years or more after treatment initiation and resulted in death. Cases of PML in patients treated with adalimumab, etanercept, or infliximab occurred in patients treated for conditions other than psoriasis and were confounded by the use of other immunosuppressive therapies or were not confirmed PML cases. Limitations AERS data are limited because of an underreporting of spontaneous post-marketing adverse events and variable quality and quantity of information provided. Conclusions These cases suggest that prolonged efalizumab therapy is a risk factor for PML. Although the cases reported treatment for longer than 3 years, a specific treatment duration that does not place patients at risk for PML has not been defined.

Aliment Pharmacol Ther 31, 1028–1035 Summary Background Natalizumab is a recombinant monoclonal antibody approved for the treatment of patients with multiple sclerosis and patients with Crohn’s disease. Because of its immunosuppressive effects, natalizumab has been associated with a number of atypical and opportunistic infections. Aim To describe and summarize six spontaneously reported post-marketing cases of clinically significant drug induced-liver injury associated with natalizumab use. Methods The FDA maintains a database of adverse event reports (AERS). We searched the AERS database for reports of serious liver injury associated with natalizumab use from November 2004, when the drug was approved, through 30 June 2008. Results The search resulted in six spontaneously reported post-marketing cases of severe drug-induced liver injury. Four of six patients developed liver injury with elevations of serum transaminases and hyperbilirubinemia after only a single infusion of natalizumab. One of these patients experienced repeated increases of aminotransferases and bilirubin when natalizumab was re-administered. Conclusions Serious hepatic injury may occur in association with natalizumab use. Health professionals should be alerted to possible serious liver injury in patients receiving natalizumab.

Sodium Phosphate Tablets and Acute Phosphate Nephropathy

Telithromycin is the first of a new class of ketolide antibiotics with increased activity against penicillin-resistant and erythromycin-resistant pneumococci. This agent received approval by the United States Food and Drug Administration (FDA) in 2004 for treatment of upper and lower respiratory infections. Following market introduction, spontaneous reports of telithromycin-associated hepatotoxicity, including frank liver failure, were received. To address these reports, an ad hoc group with expertise in spontaneous adverse events reporting and experience in evaluating drug-induced liver injury was formed, including members of the FDA, other federal agencies, and academia. The primary objective of this group was to adjudicate case reports of hepatic toxicity for causal attribution to telithromycin. After an initial screening of all cases of liver injury associated with telithromycin reported to FDA as of April 2006 by one of the authors, 42 cases were comprehensively reviewed and adjudicated. Five cases included a severe outcome of either death (n = 4) or liver transplantation (n = 1); more than half were considered highly likely or probable in their causal association with telithromycin. Typical clinical features were: short latency (median, 10 days) and abrupt onset of fever, abdominal pain, and jaundice, sometimes with the presence of ascites even in cases that resolved. Concurrence in assignment of causality increased after agreement on definitions of categories and interactive discussions. Conclusion: Telithromycin is a rare cause of drug-induced liver injury that may have a distinctive clinical signature and associated high mortality rate. Consensus for attribution of liver injury to a selected drug exposure by individual experts can be aided by careful definition of terminology and discussion. (HEPATOLOGY 2009;49:250-257.)

Drug-induced liver injury (DILI) is of major interest to hepatologists and clinicians in general, patients, government regulators, and the pharmaceutical industry. Understanding why this form of injury occurs only in certain individuals has major implications for the development and availability of drug therapies and in the prevention of these events. A single controlled clinical trial may be unlikely to show cases of such rare events, but in the aggregate, clinical trials offer a unique resource for learning more about individual susceptibility and developing truly predictive new biomarkers for DILI. We pose the question as to whether clinical trials could be modified or improved to provide data that would better answer some of the outstanding issues. At a recent (March 2008) public meeting, experts from academia, industry, and regulatory bodies discussed several major issues regarding liver safety in clinical trials including: what signals of liver injury should justify stopping administration of study drug or allowing it to continue; if deliberate rechallenge should be done and under what circumstances; whether patients with liver disease should be included in clinical trials; and what kinds of new biomarkers will be needed to answer these questions more clearly. Past clinical trials have not provided data to settle those issues, and reliance has defaulted to consensus of expert opinions. Modified and better clinical trials with standardized collection of data and biospecimens are probably the best source of new and potentially valuable information to supplant current rules based on consensus of expert opinions and to understand by what mechanisms and how to distinguish those individuals who are susceptible to severe DILI.

Editors' Note: Correspondence in Writ e Click this week references the article by Drs. Simms, Kortepeter, and Avigan, “Lamotrigine and aseptic meningitis.” Drs. Tatum and French point out that most physicians will never see a case of lamotrigine-associated aseptic meningitis and that, in pregnancy, lamotrigine has one of the safest clinical profiles despite its category C ranking. Dr. Sethi cautions that aseptic meningitis should still be a diagnosis of exclusion in any patient and that physicians should not be deterred from using this highly effective medication. The authors agree with Dr. Sethi on both points and offer that data collected since lamotrigine was approved in 1994 support that aseptic meningitis is a very rare complication. Megan Alcauskas, MD, and Robert C. Griggs, MD # {#article-title-2} An association between lamotrigine and aseptic meningitis is predicated on a complete clinical and CSF investigation …