Metabolism Profiles of Trimethoprim in Idiosyncratic Adverse Drug Reaction-Affected Tissues.

Idiosyncratic adverse drug reactions are unpredictable and thought to have an underlying genetic etiology. With the completion of the human genome and HapMap projects, together with the rapid advances in genotyping technologies, we have unprecedented capabilities in identifying genetic predisposing factors for these relatively rare, but serious, reactions. The main roadblock to this is the lack of sufficient numbers of well-characterized samples from patients with such reactions. This is now beginning to be solved through the formation of international consortia, including developing novel ways of identifying and recruiting patients affected by these reactions, both prospectively and retrospectively. This has been led by the research on abacavir hypersensitivity - its association with HLA-B*5701 forms the gold standard of how we need to identify associations and implement them in clinical practice. Strong genetic predisposing factors have also been identified for hypersensitivity reactions such as are associated with carbamazepine, allopurinol, flucloxacillin, and statin-induced myopathy. However, for most other idiosyncratic adverse drug reactions, the genetic effect sizes have been low to moderate, although this may partly be due to the fact that only small numbers have been investigated and limited genotyping strategies have been utilized. It may also indicate that genetic predisposition will be dependent on multiple genes, with complex interactions with environmental factors. Irrespective of the strength of the genetic associations identified with individual idiosyncratic adverse drug reactions, it is important to undertake functional investigations to provide insights into the mechanism(s) of how the drug interacts with the gene variant to lead to a phenotype, which can take a multitude of clinical forms with variable severity. Such investigations will be essential in preventing the burden caused by idiosyncratic reactions, both in healthcare and in industry.

11.31 - Idiosyncratic Adverse Drug Reactions

Bioactivation of Trimethoprim to Protein-Reactive Metabolites in Human Liver Microsomes.

Although idiosyncratic adverse drug reactions are rare, they are still a major concern to patient safety. Reactive metabolites are widely accepted as playing a pivotal role in the pathogenesis of idiosyncratic adverse drug reactions. While there are today well established strategies for the risk assessment of stable metabolites within the pharmaceutical industry, there is still no consensus on reactive metabolite risk assessment strategies. This is due to the complexity of the mechanisms of these toxicities as well as the difficulty in identifying and quantifying short-lived reactive intermediates such as reactive metabolites. In this review, reactive metabolite risk and hazard assessment approaches are discussed, and their pros and cons highlighted. We also discuss the nature of idiosyncratic adverse drug reactions, using acetaminophen and nefazodone to exemplify the complexity of the underlying mechanisms of reactive metabolite mediated hepatotoxicity. One of the key gaps moving forward is our understanding of and ability to predict the contribution of immune activation in idiosyncratic adverse drug reactions. Sections are included on the clinical phenotypes of immune mediated idiosyncratic adverse drug reactions and on the present understanding of immune activation by reactive metabolites. The advances being made in microphysiological systems have a great potential to transform our ability to risk assess reactive metabolites, and an overview of the key components of these systems is presented. Finally, the potential impact of systems pharmacology approaches in reactive metabolite risk assessments is highlighted.

Drug-Induced Liver Injury, Dosage, and Drug Disposition: Is Idiosyncrasy Really Unpredictable?

Drug-Induced Rhabdomyolysis Atlas (DIRA) for idiosyncratic adverse drug reaction management

ABSTRACTIntroduction: Animal toxicity studies used to assess the safety of new candidate pharmaceuticals prior to their progression into human clinical trials are unable to assess the risk of non-pharmacologically mediated idiosyncratic adverse drug reactions (ADRs), the most frequent of which are drug-induced liver injury and cardiotoxicity. Idiosyncratic ADRs occur only infrequently and in certain susceptible humans, but are caused by many hundreds of different drugs and may lead to serious illness.Areas covered: Idiosyncratic ADRs are initiated by drug-related chemical insults, which cause toxicity due to susceptibility factors that manifest only in certain patients. The chemical insults can be detected using in vitro assays. These enable useful discrimination between drugs that cause high versus low levels of idiosyncratic ADR concern. Especially promising assays, which have been described recently in peer-reviewed scientific literature, are highlighted.Expert opinion: Effective interpretation of in vitro toxicity data requires integration of endpoints from multiple assays, which each address different mechanisms, and must also take account of human systemic and tissue drug exposure in vivo. Widespread acceptance and use of such assays has been hampered by the lack of correlation between idiosyncratic human ADR risk and toxicities observed in vivo in animals.

Idiosyncratic Adverse Drug Reactions

Introduction Idiosyncratic adverse drug reactions (IADRs) or drug hypersensitivity reactions (DHRs) represent a major health problem because they are unpredictable and can be severe with potential life-long or even lethal consequences. Their pathophysiology is not clear but thought to be immune mediated, supported by the significant statistical association of these reactions with specific alleles of the human leukocyte antigen (HLA) gene. Area covered This comprehensive update review summarizes the currently available evidence on the role of HLA gene locus in IADRs and discusses the present understanding of the pathophysiology of IADRs. We searched the available literature in PubMed and Google Scholar with no date restriction for publications on HLA and adverse drug reactions. Findings are summarized and discussed in the context of the currently available evidence. Expert opinion The role of the immune system in IADRs and the role of pharmacogenetic testing in this field is evident. HLA genetic testing is very promising in the management of these reactions. Many obstacles seem to prevent pharmacogenetic testing to meet its full potential including cost and health care providers’ education. Further work in needed to provide more evidence and allow widespread use of pharmacogenetic testing in the clinical practice.

Modification of endogenous proteins by drugs and drug metabolites are thought to be a cause of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP) is a commonly prescribed antibiotic that has been implicated in IADRs; however, there is no known mechanism by which this drug or its metabolites modify proteins. This study describes the results of screening trimethoprim and its primary metabolites for the ability to covalently modify human serum albumin (HSA). The first step of the screen was in vitro reactions of the compounds with HSA followed by western blotting with antisera specific to drug-modified proteins. Compounds with positive signal in the western blot were then screened using an untargeted peptide profiling method to discover modified peptides. This strategy identified two sites in HSA that are modified by incubation with a TMP metabolite, α-hydroxy trimethoprim (Cα-OH-TMP).

Idiosyncratic adverse drug reactions (IADRs) in humans can result in a broad range of clinically significant toxicities leading to attrition during drug development as well as postlicensing withdrawal or labeling. IADRs arise from both drug and patient related mechanisms and risk factors. Drug related risk factors, resulting from parent compound or metabolites, may involve multiple contributory mechanisms including organelle toxicity, effects related to compound disposition, and/or immune activation. In the current study, we evaluate an in vitro approach, which explored both cellular effects and covalent binding (CVB) to assess IADR risks for drug candidates using 36 drugs which caused different patterns and severities of IADRs in humans. The cellular effects were tested in an in vitro Panel of five assays which quantified (1) toxicity to THLE cells (SV40 T-antigen-immortalized human liver epithelial cells), which do not express P450s, (2) toxicity to a THLE cell line which selectively expresses P450 3A4, (3) cytotoxicity in HepG2 cells in glucose and galactose media, which is indicative of mitochondrial injury, (4) inhibition of the human bile salt export pump, BSEP, and (5) inhibition of the rat multidrug resistance associated protein 2, Mrp2. In addition, the CVB Burden was estimated by determining the CVB of radiolabeled compound to human hepatocytes and factoring in both the maximum prescribed daily dose and the fraction of metabolism leading to CVB. Combining the aggregated results from the in vitro Panel assays with the CVB Burden data discriminated, with high specificity (78%) and sensitivity (100%), between 27 drugs, which had severe or marked IADR concern, and 9 drugs, which had low IADR concern, we propose that this integrated approach has the potential to enable selection of drug candidates with reduced propensity to cause IADRs in humans.

It is generally accepted that bioactivation of relatively inert functional groups (toxicophores) to reactive metabolites is an obligatory step in the pathogenesis of certain idiosyncratic adverse drug reactions (IADRs). IADRs cannot be detected in regulatory animal toxicity studies and, given their low frequency of occurrence in humans (1 in 10,000 to 1 in 100,000), they are often not detected until the drug has gained broad exposure in a large patient population. The detection of IADRs during late clinical trials or after a drug has been released can lead to an unanticipated restriction in its use, and even in its withdrawal. To date, there is neither a consistent nor a well-defined link between bioactivation and IADRs; however, the potential does exist for these processes to be causally related. Thus, the formation of reactive metabolites with a drug candidate is generally considered a liability in most pharmaceutical companies. Procedures have been implemented to evaluate bioactivation potential of new drug candidates with the goal of eliminating or minimizing reactive metabolite formation by rational structural modification of the lead chemical class. While such studies have proven extremely useful in the retrospective analysis of bioactivation pathways of toxic drugs and defining toxicophores, their ability to accurately predict the IADR potential of new drug candidates has been challenged, given that several commercially successful drugs form reactive metabolites, yet, they are not associated with a significant incidence of IADRs. In this article, we review the basic methodology that is currently utilized to evaluate the bioactivation potential of new compounds, with particular emphasis on the advantages and limitation of these assays. Plausible reasons for the excellent safety record of certain drugs susceptible to bioactivation are also explored. Overall, these observations provide valuable guidance in the proper use of bioactivation assessments when selecting drug candidates for development.

The drug-metabolizing capacity of the liver is well known but cannot account for most idiosyncratic adverse drug reactions. Of the extrahepatic sources of reactive drug metabolites, the neutrophil has received the most attention because of its vast numbers and robust oxidizing machinery. Many drugs associated with autoimmunity are susceptible to oxidative transformation by the enzymatic action of myeloperoxidase, a protein released into the extracellular environment when neutrophils are activated. Production of the resulting drug metabolites within lymphoid organs maximizes their immune-perturbing effects. Mechanisms proposed for the initiation of drug-induced blood dyscrasias, hypersensitivity reactions, or lupus-like symptoms center around three views: (1) presentation of the implicated compound in the major histocompatibility complex of antigen-presenting cells via direct binding or after processing as a hapten bound to self-macromolecules, (2) direct cytotoxicity, or (3) interference in the development of T-cell tolerance in the thymus. How participation of reactive drug metabolites in these processes might lead to symptomatic disease is discussed.

Human leukocyte antigen and idiosyncratic adverse drug reactions

Background and importanceAllergies should be visible on all patient specific pages or screens of the electronic medical record in the hospital information system. The computerised physician order entry system must...