Drug-induced liver injury: a safety review

Introduction: Idiosyncratic drug-induced liver injury (DILI) remains one of the most important causes of drug attrition both in the early phases of clinical drug development and in the postmarketing scenario. This is because, in spite of emerging data on genetic susceptibility variants associated to the risk of hepatotoxicity, the precise identification of the individual who will develop DILI when exposed to a given drug remains elusive.

Areas covered: In this review, we have addressed recent progress made and initiatives taken in the field of DILI from a safety perspective through a comprehensive search of the literature.

Expert opinion: Despite the substantial progress made over this century, new approaches using big data analysis to characterize the true incidence of DILI are needed and to categorize the drugs’ hepatotoxic potential. Genetic studies have highlighted the role of the adaptive immune system yet the mechanisms leading adaptation versus progression remain to be elucidated. There is a compelling need for development and qualification of sensitive, specific, and affordable biomarkers in DILI to foster drug development, patient treatment stratification and, improvement of causality assessment methods. Gaining mechanistic insights in DILI is essential to uncover therapeutic targets and design prospective clinical trials with appropriate endpoints.     

Highlights of drug - and herb- induced liver injury in the literature from 2016: how best to translate new information into clinical practice?

Introduction: Over 1500 papers on drug-induced liver injury (DILI) and herb-induced liver injury (HILI) were published in 2016, many of which have the potential to impact clinical practice.

Areas covered: Clinical studies and case series that lent themselves to new concepts in diagnosing, and treating DILI were selected for inclusion. Epidemiology of DILI in large prospective registries was highlighted. Causality assessment of drug hepatotoxicity remains challenging, as seen with cases of OxyELITE Pro (OEP). In 2016 updates to the Roussel Uclaf Causality Assessment Method (RUCAM) were published to aid in the accuracy of diagnosing DILI/HILI. New reports of established hepatotoxins were again discussed in 2016, including genetic risk factors for DILI with respect to antituberculous agents.

Expert opinion: 2016 marked a turning point in how much credence should be placed in the current causality assessment for DILI/HILI cases. Many recognized hepatotoxins are backed by a relatively few number of literature reports. Danan and Teschke make a strong case that an updated RUCAM should remain the gold standard for diagnosing DILI/HILI going forward, although the role of expert opinion is often still needed in cases where RUCAM falls short. The field of chemoinformatics continues to evolve while we await a truly predictive and diagnostic DILI biomarker.     

Tubulin inhibitors in non-small cell lung cancer: looking back and forward

Introduction: Although the advent of target therapy for lung cancer has brought about outstanding results, this benefit is confined to a subgroup of molecularly selected patients, whereas for most non-small cell lung cancer (NSCLC) patients, chemotherapy still represents the milestone of treatment. Since their introduction into clinics, microtubule targeting agents (MTA), including vinca alkaloids and taxanes, have been extensively used for NSCLC in different settings and combinations.

Areas Covered: In this review, MTA are classified according to their mechanism of action, with a focus on the most common mechanisms of resistance. Moreover, an overview of the most remarkable clinical data regarding MTA in adjuvant, neoadjuvant and advanced setting is provided. Finally, the novel mitotic kinases inhibitors are described according to their different mechanism of action and clinical activity compared to MTA.

Expert Opinion: Unfortunately, the awaited benefit deriving from the actually available chemotherapeutic regimens for advanced NSCLC has reached a plateau. In this scenario, the identification of reliable predictive biomarkers represents a major challenge. Moreover, different schedules for MTA administration are currently under investigation, such as the combination of MTA with other drugs able to bypass the resistance derived from the ‘mitotic slippage’ and the use of metronomic administration of spindle poisons with anti-angiogenic or immunomodulatory agents.     

Characteristics associated with drug-induced liver injury from interferon beta in multiple sclerosis patients

Objective: To identify and characterize drug-induced liver injury (DILI) associated with IFN-β in multiple sclerosis (MS) using recommended criteria.

Methods: This retrospective, mixed methods design included a cohort of IFN-β exposed MS patients from British Columbia (BC), Canada and a series of DILI cases from other Canadian provinces and two adverse drug reaction (ADR) networks (USA and Sweden). Associations between sex, age and IFN-β product, and DILI were explored in BC cohort using Cox proportional hazard analyses. Characteristics, including the time to DILI, were compared between sites.

Results: In BC, 18/942 (1.9%) of IFN-β exposed MS patients met criteria for DILI, with a trend toward an increased risk for women and those exposed to IFN-β-1a SC (44 mcg 3 × weekly) (adjusted Hazard Ratios: 3.15;95% CI:0.72 – 13.72, p = 0.13 and 6.26;95%CI:0.78 – 50.39, p = 0.08, respectively). Twenty-four additional cases were identified from other sites; the median time to DILI was comparable between BC and other Canadian cases (105 and 90 days, respectively), but longer for the ADR network cases (590 days, p = 0.006).

Conclusions: Approximately 1 in 50 IFN-β exposed patients developed DILI in BC, Canada. Identification of DILI cases from diverse sources highlighted that this reaction occurs even after years of exposure.     

Proton pump inhibitors and clopidogrel: is it a significant drug interaction?

Importance of the field: Clopidogrel is indicated as part of a dual antiplatelet therapy (DAT) with aspirin for the prevention of cardiac related events in acute coronary syndromes particularly in patients undergoing percutaneous coronary intervention. Recently, there have been reports of a clinically significant drug interaction between clopidogrel and proton pump inhibitors (PPI), which are frequently co-prescribed to prevent DAT associated gastrointestinal (GI) bleeding.

Areas covered in this review: This review evaluates the risk of GI bleeding associated with DAT and the rationale for the use of PPI. This review also describes the pharmacokinetic and pharmacodynamic basis for the interaction and evaluates its significance on clinical outcomes. An extensive literature search on PubMed from January 1980 to August 2009 was performed. Additionally, abstracts and presentations from key cardiology meetings and press releases were reviewed for relevant studies related to the interaction.

What the reader will gain: At the end of the review, readers should have a complete understanding of the interaction and steps that can be taken to limit the interaction.

Take home message: There is a mechanistic basis and pharmacodynamic data supporting an interaction between PPIs, particularly omeprazole and clopidogrel. The clinical significance of this interaction is, however, still a subject of intense debate and ongoing research.     

Clinical and causality assessment in herbal hepatotoxicity

Introduction: Herbal hepatotoxicity represents a poorly understood, neglected and multifaceted disease with numerous confounding variables and missing established causality in the majority of cases. This review discusses overt shortcomings in its clinical and causality assessment and suggests improvements.

Areas covered: A selective literature search of PubMed using the terms herbal hepatotoxicity, herb-induced liver injury, drug hepatotoxicity and drug-induced liver injury was performed to identify published case reports, spontaneous case reports, case series and review articles regarding hepatotoxicity due to herbs, herbal drugs and herbal dietary supplements. Covered areas focused on confounding variables related to the documentation of the herbal product and the clinical course, hepatotoxicity and reexposure criteria, temporal association, comedication and alternative causes with special attention to preexisting diseases of the liver, bile ducts and the pancreas. Of particular interest were recent discussions of approaches designed and validated for hepatotoxicity causality, such as the scale of CIOMS (Council for International Organizations of Medical Sciences).

Expert opinion: The authors call for substantial improvements in data quality of herbal products and case characteristics and strongly recommend using the CIOMS scale to assess causality in suspected herbal hepatotoxicity.     

Statin drug interactions and related adverse reactions

Introduction: Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, their possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment.

Areas covered: This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions and related adverse reactions.

Expert opinion: Avoiding drug–drug interactions and consequent adverse drug reactions is essential in order to optimize compliance, and thus improve the treatment of patients at high cardiovascular risk. The different pharmacokinetic profiles among statins should be carefully considered, in order to understand the possible spectrum of drug interactions. The growing trend toward earlier statin treatment for the prevention of cardiovascular disease means that physicians must anticipate future polypharmacy when their patients require additional medications for comorbid conditions.     

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

Introduction: Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI.

Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver.

Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs.     

Metabolic activation and drug‐induced liver injury: in vitro approaches for the safety risk assessment of new drugs

Drug‐induced liver injury (DILI) is a significant leading cause of hepatic dysfunction, drug failure during clinical trials and post‐market withdrawal of approved drugs. Many cases of DILI are unexpected reactions of an idiosyncratic nature that occur in a small group of susceptible individuals. Intensive research efforts have been made to understand better the idiosyncratic DILI and to identify potential risk factors. Metabolic bioactivation of drugs to form reactive metabolites is considered an initiation mechanism for idiosyncratic DILI. Reactive species may interact irreversibly with cell macromolecules (covalent binding, oxidative damage), and alter their structure and activity. This review focuses on proposed in vitro screening strategies to predict and reduce idiosyncratic hepatotoxicity associated with drug bioactivation. Compound incubation with metabolically competent biological systems (liver‐derived cells, subcellular fractions), in combination with methods to reveal the formation of reactive intermediates (e.g., formation of adducts with liver proteins, metabolite trapping or enzyme inhibition assays), are approaches commonly used to screen the reactivity of new molecules in early drug development. Several cell‐based assays have also been proposed for the safety risk assessment of bioactivable compounds. Copyright © 2015 John Wiley & Sons, Ltd.     

In silico models for drug-induced liver injury--current status

INTRODUCTION: Drug-induced liver injury (DILI) is one of the most important reasons for drug attrition at both pre-approval and post-approval stages. Therefore, it is crucial to develop methods that will detect potential hepatotoxicity among drug candidates as early and quickly as possible. However, the complexity of hepatotoxicity endpoint makes it very difficult to predict. In addition, there is still a lack of sensitive and specific biomarkers for DILI that consequently leads to a scarcity of reliable hepatotoxic data, which are the key to any modelling approach. AREAS COVERED: This review explores the current status of existing in silico models predicting hepatotoxicity. Over the past decade, attempts have been made to compile hepatotoxicity data and develop in silico models, which can be used as a first-line screening of drug candidates for further testing. EXPERT OPINION: Most of the predictive methods discussed in this review are based on the structural properties of chemicals and do not take into account genetic and environmental factors; therefore, their predictions are still uncertain. To improve the predictability of in silico models for DILI, it is essential to better understand its mechanisms as well as to develop sensitive toxicogenomics biomarkers, which show relatively good differentiation between hepatotoxins and non-hepatotoxins.     

Does the use of lapatinib increase the risk of fatigue and hepatic toxicities in patients with solid tumors? A critical literature review and meta-analysis

Objective: A systematic review and meta-analysis of fatigue and hepatic adverse events associated with lapatinib use in solid tumor patients were performed.

Research design and methods: Eligible studies included randomized Phase II and III trials of patients with solid tumors taking lapatinib. They described events of fatigue, elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. Our search yielded 380 potentially relevant citations on lapatinib from PubMed/Medline, CENTRAL Cochrane registry and ASCO meeting library.

Results: After exclusion of ineligible studies, a total of 15 clinical trials were included in the meta-analysis. The relative risk (RR) of all-grade fatigue, elevated ALT, AST and total bilirubin were 0.99 (95% CI 0.87 – 1.13; p = 0.87), 1.12 (95% CI 0.87 – 1.44; p = 0.55), 0.79 (95% CI 0.43 – 1.45; p = 0.44), 5.17 (95% CI 0.18 – 149.81; p = 0.34), respectively. Exploratory subgroup analysis showed no effect of comparator regimen on the RR of the relevant adverse events.

Conclusions: This meta-analysis demonstrated that the evidence for a true increased risk of hepatotoxicity or fatigue with lapatinib-based treatment compared to control is not yet fully convincing. Future studies should investigate this risk further. Clinicians must be aware of these risks and perform regular clinical monitoring.     

Interactions between oral antineoplastic agents and concomitant medication: a systematic review

Introduction: In recent years, the number of oral antitumoral agents has considerably increased. Oral administration increases the risk of interactions, because most oral anticancer drugs are taken on a daily basis. Interactions can increase exposure to antitumoral agents or cause treatment failure. Many antitumoral drugs undergo enzymatic metabolism by cytochrome P450. As some act as inducers or inhibitors of one or more isoenzymes, they can lead to decreases or increases in plasma concentrations of concomitant drugs. Hence, cytostatic drugs can act not only as victims but also as perpetrators. P-glycoprotein, an efflux transporter, can also be involved in pharmacokinetic interactions.

Areas covered: A Medline search was performed to summarize the available evidence of the most clinically relevant interactions between oral chemotherapy agents and other drugs. The search covered the period from 1966 until August 2012 for each antitumoral drug using the medical subject headings ‘Drug Interactions' OR ‘Pharmacokinetics'. While the present review is not exhaustive, it aims to increase clinicians' awareness of potential drug–drug interactions.

Expert opinion: As cancer patients are often polymedicated and treated by different physicians, the risk of drug interactions between antitumoral agents and other medications is high. More clinical interaction studies are encouraged to ensure appropriate antineoplastic pharmacokinetics in clinical practice.     

Current pharmacotherapy for the treatment of dyslipidemia associated with HIV infection

ABSTRACT

Introduction: Cardiovascular disease is an important cause of morbidity and mortality in persons with human immunodeficiency virus (PWH). The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in PWH compared to uninfected persons. Dyslipidemia is a critical link in the pathogenesis of ASCVD in PWH. Chronic inflammation associated with HIV infection may drive both dyslipidemia and ASCVD.

Areas covered: The authors review the evidence for using lipid-lowering therapy in PWH and includes an overview of the utility and complexity of using statins in PWH, in particular, drug interactions, safety, and efficacy. In addition, data covering alternate therapies like omega-3 fatty acids, fibrates, niacin, ezetimibe, and PCSK-9 inhibitors are reviewed.

Expert opinion: Dyslipidemia is a common problem in PWH. The risk of ASCVD is higher in PWH. Lipid-lowering therapy reduces the risk of ASCVD, but clinical endpoint trials are lacking in PWH. Statin therapy is the mainstay of primary prevention for ASCVD. The timing of when to initiate primary prevention with statins in PWH is unclear. Beyond statins, there are limited data that other lipid-lowering agents have utility in PWH. Ongoing trials like the REPRIEVE trial will inform the community about the optimal approach to lipid-lowering therapy in PWH.     

Statin intolerance – a question of definition

Introduction: Statin therapy is the backbone of pharmacologic therapy for low-density lipoproteins cholesterol lowering and plays a pivotal role in cardiovascular disease prevention. Statin intolerance is understood as the inability to continue using a statin to reduce individual cardiovascular risk sufficiently, due to the development of symptoms or laboratory abnormalities attributable to the initiation or dose escalation of a statin. Muscle symptoms are the most common side effects observed.

Areas covered: The main aim of this article is to present a review on published definitions of statin intolerance. In addition, a brief review on clinical aspects and risk factors of statin intolerance is provided and features for a common definition for statin intolerance are suggested.

Expert opinion: A definition of statin intolerance by major drug regulatory agencies is not available. In clinical studies, different definitions are chosen and results are not comparable; different medical associations do not agree on one common definition. There is an unmet need to establish a common definition of statin intolerance to ensure an appropriate clinical use of this important drug class. Further work is required to develop a consensus definition on statin intolerance that could have significant positive impact on both research and clinical management.     

Prescribing issues in elderly individuals living with HIV

ABSTRACT

Introduction: Combined antiretroviral therapy has transformed HIV infection into a chronic disease thus people living with HIV (PLWH) live longer. As a result, the management of HIV infection is becoming more challenging as elderly experience age-related comorbidities leading to complex polypharmacy and a higher risk for drug-drug or drug–disease interactions. Furthermore, age-related physiological changes affect pharmacokinetics and pharmacodynamics thereby predisposing elderly PLWH to incorrect dosing or inappropriate prescribing and consequently to adverse drug reactions and the subsequent risk of starting a prescribing cascade.

Areas covered: This review discusses the demographics of the aging HIV population, physiological changes and their impact on drug response as well as comorbidities. Particular emphasis is placed on common prescribing issues in elderly PLWH including drug–drug interactions with antiretroviral drugs. A PubMed search was used to compile relevant publications until February 2019.

Expert opinion: Prescribing issues are highly prevalent in elderly PLWH thus highlighting the need for education on geriatric prescribing principles. Adverse health outcomes potentially associated with polypharmacy and inappropriate prescribing should promote interventions to prevent harm including medication reconciliation, medication review, and medication prioritization according to the risks/benefits for a given patient. A multidisciplinary team approach is recommended for the care of elderly PLWH.     

Drug safety assessment of oral formulations of ketoconazole

Introduction: Ketoconazole was the first broad-spectrum oral antifungal approved by the FDA in 1981. Post-marketing reports of drug-related hepatotoxicity, endocrine dysregulation and drug interactions resulted in market withdrawal of the drug in some countries and strict product relabeling in others.

Areas covered: This drug safety review summarizes reports of oral ketoconazole-related adverse events retrieved from a search of the PubMed database using the search strategy ‘ketoconazole OR Nizoral AND hepat*’, references from relevant publications, and data from the FDA Adverse Event Reporting System.

Expert opinion: Although oral ketoconazole is effective in treating fungal infections, the potential for drug interactions, endocrine dysregulation, and hepatotoxicity may outweigh its benefits. Newer oral antifungals have similar or greater efficacy in treating dermatologic conditions and are associated with less risk. Likewise, newer agents with specific targets and fewer drug interactions have been developed to treat systemic fungal infections. Therefore, by the time ketoconazole prescribing guidelines were amended, its use had already largely been replaced with newer antifungals. Being that ketoconazole was the first broad-spectrum oral antifungal, experience with the drug made patient safety, and especially hepatic safety, an important consideration in future antifungal development.     

What is the impact of the 2017 cochrane systematic review and meta-analysis that evaluated the use of PCSK9 inhibitors for lowering cardiovascular disease and mortality?

Introduction: In 2017, Schmidt et al. conducted a Cochrane systematic review and meta-analysis to evaluate the effect of using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to reduce low-density-lipoprotein- cholesterol (LDL-C) and cardiovascular disease (CVD). The Cochrane review was a systematic review and meta-analysis of 20 randomized, double-blinded trials that compared the use of PCSK9 inhibitors with statins/ezetimibe, ezetimibe, or placebo for a treatment duration of at least 24 weeks. The use of PCSK9 inhibitors lowered the risk for CVD (OR 0.86 (0.80 to 0.92)) but not mortality (OR 1.02 (0.91 to 1.14)) when compared to placebo.

Areas covered: The following article evaluates the recently published Cochrane review and clarifies the efficacy of PCSK9 inhibitors for improving cardiovascular morbidity and mortality.

Expert opinion: The Cochrane review discussed suggests that PCSK9 inhibitors are effective in lowering LDL-C and the risk of CVD but not the risk of mortality. The higher price of PCSK9 inhibitors is a further deterrent for using them as a substitute for statins – cholesterol lowering medications with history showing they lower mortality. Statins should remain the gold-standard cholesterol-lowering drug class until PCSK9 inhibitors become more affordable and demonstrate consistent efficacy for reducing CVD and mortality.     

Hepatotoxicity reports in the FDA adverse event reporting system database: A comparison of drugs that cause injury via mitochondrial or other mechanisms

Drug-induced liver injury (DILI) is a leading reason for preclinical safety attrition and post-market drug withdrawals. Drug-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI, especially in idiosyncratic liver injury. This study examined liver injury reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of toxicity. The frequency of hepatotoxicity was determined at a group level and individual drug level. A reporting odds ratio (ROR) was calculated as the measure of effect. Between the two DILI groups, reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43 (95% CI 1.42–1.45; P < 0.0001) times higher odds compared to drugs associated with non-mitochondrial mechanisms of toxicity. Antineoplastic, antiviral, analgesic, antibiotic, and antimycobacterial drugs were the top five drug classes with the highest ROR values. Although the top 20 drugs with the highest ROR values included drugs with both mitochondrial and non-mitochondrial injury mechanisms, the top four drugs (ROR values > 18: benzbromarone, troglitazone, isoniazid, rifampin) were associated with mitochondrial mechanisms of toxicity. The major demographic influence for DILI risk was also examined. There was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1 ± 18.33 (SD)] compared to non-mitochondrial mechanisms [48 ± 19.53 (SD)] (P < 0.0001), suggesting that age may play a role in susceptibility to DILI via mitochondrial mechanisms of toxicity. Univariate logistic regression analysis showed that reports of liver injury were 2.2 (odds ratio: 2.2, 95% CI 2.12–2.26) times more likely to be associated with older patient age, as compared with reports involving patients less than 65 years of age. Compared to males, female patients were 37% less likely (odds ratio: 0.63, 95% CI 0.61–0.64) to be subjects of liver injury reports for drugs associated with mitochondrial toxicity mechanisms. Given the higher proportion of severe liver injury reports among drugs associated with mitochondrial mechanisms of toxicity, it is essential to understand if a drug causes mitochondrial toxicity during preclinical drug development when drug design alternatives, more clinically relevant animal models, and better clinical biomarkers may provide a better translation of drug-induced mitochondrial toxicity risk assessment from animals to humans. Our findings from this study align with mitochondrial mechanisms of toxicity being an important cause of DILI, and this should be further investigated in real-world studies with robust designs.