Showing papers in "Expert Opinion on Drug Metabolism & Toxicology in 2017"
TL;DR: Apigenin has value as a good cellular regulator in cancer, especially cancers of the gastrointestinal tract, and novel carriers would need to be developed to enhance the oral bioavailability of apigenin.
Abstract: Introduction: Apigenin, a natural flavone, is widely distributed in plants such as celery, parsley and chamomile. It is present principally as glycosylated in nature. Higher intake of apigenin could reduce the risk of chronic diseases. It has gained particular interest in recent years as a beneficial, health-promoting agent with low intrinsic toxicity.Areas covered: This review summarizes and the absorption, distribution, metabolism and excretion (ADME) properties of apigenin, and drug-drug interaction of apigenin.Expert opinion: Since apigenin is a bioactive plant flavone and is widely distributed in common food, its consumption through the diet is recommended. Apigenin-enriched drugs are better for some chronic diseases, but may affect animal and human health if present in the daily diet. Dietary or therapeutic apigenin has value as a good cellular regulator in cancer, especially cancers of the gastrointestinal tract. Due to apigenin’s limitations on absorption and bioavailability, novel carrier...
133 citations
TL;DR: This review provides an overview of the available in silico models that have been used to predict the ADME-Tox properties of compounds and provides a comprehensive overview and summarization of the latest modeling methods and algorithms available for the prediction of physicochemical characteristics, ADME properties, and drug toxicity issues.
Abstract: Introduction: Although significant progress has been made in high-throughput screening of absorption, distribution, metabolism and excretion, and toxicity (ADME-Tox) properties in drug discovery and development, in silico ADME-Tox prediction continues to play an important role in facilitating the appropriate selection of candidate drugs by pharmaceutical companies prior to expensive clinical trials.Areas covered: This review provides an overview of the available in silico models that have been used to predict the ADME-Tox properties of compounds. It also provides a comprehensive overview and summarization of the latest modeling methods and algorithms available for the prediction of physicochemical characteristics, ADME properties, and drug toxicity issues.Expert opinion: The in silico models currently available have greatly contributed to the knowledge of screening approaches in the early stages of drug discovery and the development process. As the definitive goal of in silico molding is to predic...
113 citations
TL;DR: The encouraging clinical results ofCurcumin administration are currently limited to people with colorectal cancer, given that sufficient curcumin concentrations persist in colonic mucosa, and further studies are still warranted.
Abstract: Introduction: Curcumin has been extensively studied for its anti-cancer properties. While a diverse array of in vitro and preclinical research support the prospect of curcumin use as an anti-cancer therapeutic, most human studies have failed to meet the intended clinical expectation. Poor systemic availability of orally-administered curcumin may account for this disparity.Areas covered: This descriptive review aims to concisely summarise available clinical studies investigating curcumin pharmacokinetics when administered in different formulations. A critical analysis of pharmacokinetic- and pharmacodynamic-based interactions of curcumin with concomitantly administered drugs is also provided.Expert opinion: The encouraging clinical results of curcumin administration are currently limited to people with colorectal cancer, given that sufficient curcumin concentrations persist in colonic mucosa. Higher parent curcumin systemic exposure, which can be achieved by several newer formulations, has importan...
113 citations
TL;DR: Preliminary positive results were found in trials testing the use of NAC, mainly as an add-on treatment, in cannabis use disorder in young people, depression in bipolar disorder, negative symptoms in schizophrenia, and excoriation (skin-picking) disorder.
Abstract: Introduction: N-acetylcysteine (NAC) is widely known for its role as a mucolytic and as an antidote to paracetamol overdose. There is increasing interest in the use of NAC in the treatment of several psychiatric disorders. The rationale for the administration of NAC in psychiatric conditions is based on its role as a precursor to the antioxidant glutathione, and its action as a modulating agent of glutamatergic, dopaminergic, neurotropic and inflammatory pathways.Areas covered: This study reviews the available data regarding the use of NAC in different psychiatric disorders including substance use disorders, autism, obsessive-compulsive spectrum disorders, schizophrenia, depression, bipolar disorder. Promising results were found in trials testing the use of NAC, mainly as an add-on treatment, in cannabis use disorder in young people, depression in bipolar disorder, negative symptoms in schizophrenia, and excoriation (skin-picking) disorder. Despite initial optimism, recent findings regarding NAC e...
99 citations
TL;DR: Traditional TDM, perhaps following pre-emptive genotyping for Tac-metabolizing enzymes, must suffice for a few years before these strategies can be implemented in clinical practice.
Abstract: Introduction: Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs we...
90 citations
TL;DR: The authors present the current available knowledge regarding colistin, i.e. in vitro activity and interactions, current pharmacokinetics/pharmacodynamics (PK/PD), clinical efficacy against multidrug- resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, as well as toxicity issues, whereas the recently published newer plasmid mediated mcr-1 resistance gene is reviewed and discussed.
Abstract: Introduction: Living in the ‘era of antibiotic resistance’ and facing the threat of an ‘end to antibiotics’, physicians in the last decade have revived use of colistin, since the available literature at the clinical level was poor and limitedAreas covered: Herein, the authors present the current available knowledge regarding colistin, i.e. in vitro activity and interactions, current pharmacokinetics/pharmacodynamics (PK/PD), clinical efficacy against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, as well as toxicity issues, whereas the recently published newer plasmid mediated mcr-1 resistance gene is reviewed and discussed.Expert opinion: As proven in a big number of studies and despite their retrospective design, it is surmized that for carbapenemase producing K. pneumoniae, colistin should be given in combination with another active in vitro antibiotic and preferably meropenem/doripenem whenever the relevant minimum inhibitory concentration is ≤8 mg/L. Ho...
88 citations
TL;DR: This review summarizes the known mechanisms by which CP exerts its toxic effects on the male reproductive system and the methods utilized to prevent such effects so that it could be further investigated and applied in clinical use.
Abstract: Introduction: Cyclophosphamide (CP) is an alkylating antineoplastic agent with known toxicity to the male reproductive system.Areas covered: This review summarizes the known mechanisms by which CP ...
86 citations
TL;DR: Identification of roles for FMO1 and FMO5 in endogenous metabolism has implications for drug therapy and initiates an exciting area of research.
Abstract: Introduction: Flavin-containing monooxygenases (FMOs) play an important role in drug metabolism.Areas covered: We focus on the role of FMOs in the metabolism of drugs in human and mouse. We describe FMO genes and proteins of human and mouse; the catalytic mechanism of FMOs and their significance for drug metabolism; differences between FMOs and CYPs; factors contributing to potential underestimation of the contribution of FMOs to drug metabolism; the developmental and tissue-specific expression of FMO genes and differences between human and mouse; and factors that induce or inhibit FMOs. We discuss the contribution of FMOs of human and mouse to the metabolism of drugs and how genetic variation of FMOs affects drug metabolism. Finally, we discuss the utility of animal models for FMO-mediated drug metabolism in humans.Expert opinion: The contribution of FMOs to drug metabolism may be underestimated. As FMOs are not readily induced or inhibited and their reactions are generally detoxifications, the d...
76 citations
TL;DR: Hyperforin seems to be the major ingredient responsible for CYP and P-gp inducing activity of SJW; thus, hyperforin-free products may be future candidates to decrease SJW’s drug interactions.
Abstract: St. John's wort (SJW) is a common medicinal herb used for the treatment of mild to moderate depression. Hyperforin, one of the chief components of SJW, plays an important role in the induction of cytochrome P450 enzymes (CYP) and P-glycoprotein transporter (P-gp), and therefore, affects the pharmacokinetics of various drugs. There are several clinical studies demonstrating the interaction of SJW with the metabolism of conventional drugs which may cause life-threatening events. Areas covered: This review focuses on human studies that have evaluated pharmacokinetic alterations of conventional drugs in concomitant use with different SJW preparations. Expert opinion: SJW preparations have demonstrated clinically important interactions with several classes of conventional drugs such as immunosuppressants, anticancer agents, cardiovascular drugs, oral contraceptives, and lipid lowering agents that caused life-threatening events in several cases. The patient information label on the SJW products should provide enough information regarding the possible risk of interaction. Hyperforin seems to be the major ingredient responsible for CYP and P-gp inducing activity of SJW; thus, hyperforin-free products may be future candidates to decrease SJW's drug interactions.
70 citations
TL;DR: An overview of Bu PK is provided, with a primary focus on how known and potentially unknown drug metabolism pathways influence Bu-associated DDIs and its effects on complications after SCT.
Abstract: Introduction: Busulfan (Bu) is an alkylating agent with a limited therapeutic margin and exhibits inter-patient variability in pharmacokinetics (PK). Despite decades of use, mechanisms of Bu PK-bas...
68 citations
TL;DR: Current strategies to investigate human health risks should be modified to increase their performance for more reliable results and also new techniques such as toxicogenomics, epigenomics and single cell approaches must be integrated into genetic safety evolutions.
Abstract: Introduction: Genotoxicity and mutagenicity analyses have a significant role in the identification of hazard effects of therapeutic drugs, cosmetics, agrochemicals, industrial compounds, food additives, natural toxins and nanomaterials for regulatory purposes. To evaluate mutagenicity or genotoxicity, different in vitro and in vivo methodologies exert various genotoxicological endpoints such as point mutations, changes in number and structure of chromosomes.Areas covered: This review covered the basics of genotoxicity and in vitro/in vivo methods for determining of genetic damages. The limitations that have arisen as a result of the common use of these methods were also discussed. Finally, the perspectives of further prospects on the use of genotoxicity testing and genotoxic mode of action were emphasized.Expert opinion: The solution of actual and practical problems of genetic toxicology is inarguably based on the understanding of DNA damage mechanisms at molecular, subcellular, cellular, organ, s...
TL;DR: Most animal models indicate that intravitreal drugs have reduced half-lives and increased clearance in vitrectomized eyes, and considering existing evidence, it is important to consider vitreous and lens status when monitoring and treating patients.
Abstract: Introduction: The review aims to discuss effects of vitrectomy on pharmacokinetics of anti-vascular endothelial growth factor (anti-VEGF) agents, and attempt to provide treatment guidance.Areas cov...
TL;DR: It is of the opinion that melatonin is a promising agent in minimizing organ injuries induced by pesticides and a potent free radical scavenger with low toxicity and desirable solubility in organic and aqueous phases.
Abstract: Introduction: Pesticides are among the most important chemicals used in agriculture sector. However, their extensive use has polluted the environment and increased human vulnerability to various chronic diseases. Pesticide exposure causes genetic and epigenetic modifications, endocrine disruption, mitochondrial dysfunction and oxidative stress.Areas covered: This review is based on the literature studies currently reported on pesticide-induced toxicity and the protective role of melatonin. Scientific databases such as PubMed, Scopus and Web of Science were searched using keywords ‘pesticide’ and ‘melatonin’ up to January 2016. Full length articles related to animal and human exposure were retrieved. A total number of 181 records were obtained, and after excluding the duplicates, 97 papers were further screened on the basis of relevance to the topic.Expert opinion: Melatonin as a broad-spectrum antioxidant is able to penetrate cellular compartments specifically the mitochondria. It is a potent free...
TL;DR: This therapeutic strategy increases biogenic amine turnover, thereby generating neurotoxic aldehydes and enhanced oxidative stress, each of which influence and accelerate the course of neurodegeneration.
Abstract: Introduction: Neurotransmission by biogenic monoamines is important for brain function. Biogenic amine turnover employs the enzymes catechol-O-methyltransferase and monoamine oxidase in neuronal and glial cells. Inhibition of these enzymes elevates biogenic amine levels in the synaptic cleft. Subtype selectivity of inhibition is lost during long-term use of ‘selective’ monoamine oxidase inhibitors.Areas covered: This narrative review discusses use of monoamine oxidase inhibitors in the context with chronic neurodegeneration.Expert opinion: Antidepressant drugs increase synaptic concentrations of biogenic amines. In the aging brain, then one of the two enzymes involved in degrading synaptic amines, catechol-O-methyl transferase, increasingly catalyzes methylation processes. Therefore, metabolism by monoamine oxidase plays an incremental, predominant role in biogenic amine turnover, leading to greater oxidative stress. In patients with chronic neurodegenerative disorders, symptoms, such as depressio...
TL;DR: A critical analysis of published data on the role of OATPs in ADME and in drug–drug interactions is offered, especially focusing on OATP1A2, 1B1,1B3 and 2B1.
Abstract: Introduction: The in vivo fate and effectiveness of a drug depends highly on its absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) Organic anion transporting polypeptides (OATPs) are membrane proteins involved in the cellular uptake of various organic compounds, including clinically used drugs Since OATPs are significant players in drug absorption and distribution, modulation of OATP function via pharmacotherapy with OATP substrates/inhibitors, or modulation of their expression, affects drug pharmacokinetics Given their cancer-specific expression, OATPs may also be considered anticancer drug targetsAreas covered: We describe the human OATP family, discussing clinically relevant consequences of altered OATP function We offer a critical analysis of published data on the role of OATPs in ADME and in drug–drug interactions, especially focusing on OATP1A2, 1B1, 1B3 and 2B1Expert opinion: Four members of the OATP family, 1A2, 1B1, 1B3 and 2B1, have been characterized in detai
TL;DR: Progestins (synthetic progestational agents) are used in the management of symptomatic endometriosis both as first-line therapy and after surgery, and progestins are usually well tolerated and offer similar efficacy for the treatment of endometiosis-related CPP and prevention of recurrence with respect to other drugs.
Abstract: Endometriosis is a common benign and proliferative chronic disorder, characterized by the presence of endometrial glands and stroma outside the uterus: in particular, ectopic endometrial tissue und...
TL;DR: The evidence for current recommendations for MTX use and male fertility is reviewed, patients treated with MTX must be counseled on the likelihood of adverse effects of MTX and role of sperm cryopreservation, and future studies are needed to help elucidate the unclear evidence ofMTX effects on male fertility and pregnancy outcomes.
Abstract: Introduction: There is a high prevalence of methotrexate (MTX) use in males of reproductive age. The scope of this paper reviews what is known regarding risks to fertility and partners’ pregnancy o...
TL;DR: This review discusses the current evidence of the alterations in pharmacokinetics that can occur with aging, frailty and in people with dementia, and discusses the four primary pharmacokinetic processes (absorption, distribution, metabolism and elimination).
Abstract: Introduction: The number of people with dementia internationally is increasing. Older adults with dementia are prescribed multiple medications, both to treat dementia symptoms and to manage their other medical conditions. Dementia is correlated with increasing age and frailty; this provides insight into how the efficacy and toxicity of medications may be altered in people with dementia.Areas covered: This review discusses the current evidence of the alterations in pharmacokinetics that can occur with aging, frailty and in people with dementia. The evidence is presented via the four primary pharmacokinetic processes (absorption, distribution, metabolism and elimination). Additionally, distribution into the brain, sex considerations and potential pharmacodynamic alterations in older people with dementia are discussed.Expert opinion: While the evidence is limited, people with dementia appear to be at a higher risk of toxicity of some medications due to altered pharmacokinetic processes and pharmacody...
TL;DR: The major challenge for optimized KI dosing is the development of high-quality evidence to demonstrate a significant improvement in therapeutic outcomes and /or reduction in adverse events through appropriately designed trials in a setting where the limited KI prescribing restricts capacity to undertake prospective randomized studies.
Abstract: Introduction: Small molecule protein kinase inhibitors (KIs) are a class of drugs with complex and unconventional physiochemical and pharmacokinetic characteristics. Cytochrome P450 mediated metabolism and transporter-mediated uptake and efflux are important processes that determine KI disposition and exposure.Areas covered: We provide an overview of KI pharmacology, with a comprehensive summary of KI physiochemical and pharmacokinetic properties and description of the major sources of variability in KI pharmacokinetics focusing on common pathways involved in determining exposure. We also consider the strategies proposed to optimize KI dosing, appraise the current evidence for their use and analyze the challenges and knowledge gaps for KI dose optimization.Expert opinion: A number of strategies to optimize KI dosing have been proposed, but evidence underpinning their use is limited. The major challenge for optimized KI dosing is the development of high-quality evidence to demonstrate a significant...
TL;DR: This paper provides a comprehensive review of the main underlying mechanisms by which various drugs cause DISH, and outlines existing preclinical tools to predict it and study underlying pathways involved.
Abstract: Introduction: Drug induced steatohepatitis (DISH), a form of drug induced liver injury (DILI) is characterized by intracellular accumulation of lipids in hepatocytes and subsequent inflammatory events, in some ways similar to the pathology seen with other metabolic, viral and genetic causes of non alcoholic fatty liver disease and steatohepatitis (NAFLD and NASH).Areas covered: This paper provides a comprehensive review of the main underlying mechanisms by which various drugs cause DISH, and outlines existing preclinical tools to predict it and study underlying pathways involved. The translational hurdles of these models are discussed, with the example of an organotypic liver system designed to address them. Finally, we describe the clinical assessment and management of DISH.Expert Opinion: The complexity of the interconnected mechanistic pathways underlying DISH makes it important that preclinical evaluation of drugs is done in a physiologically and metabolically relevant context. Advanced organo...
TL;DR: With deeper understanding of the mechanisms of the adverse cardiac effects and identification of driver mutations causing these effects, personalized cancer therapy to limit cardiotoxic effects can be achieved, such as with the cardioprotectant dexrazoxane.
Abstract: With advances in clinical oncology, the burden of morbidity and mortality for cancer survivors due to the cardiac side effects of the chemotherapy is steadily increasing. Treatment-related cardiac damage is progressive and often irreversible. Primary prevention of cardiotoxicity during treatment is possible with strategies like limiting the cumulative anthracycline dose, the use of anthracycline structural analogs, and especially cardioprotective agents. Areas covered: This review covers the various cardiotoxic chemotherapeutic agents, the pathophysiology of cardiotoxicity due to anthracyclines, and the clinical and subclinical presentations and progression of childhood anthracycline cardiotoxicity. We also discuss preventive measures and strategies, especially the cardioprotectant agent dexrazoxane where there is strong evidence-based support for its use with anthracycline chemotherapy. However, there is a paucity of evidence-based recommendations for diagnosing and treating cancer therapy-induced cardiovascular complications. Finally, we discuss the potential of cardio-oncology. Expert opinion: There is no 'safe' anthracycline dose if the goal is normal long-term cardiovascular status but higher lifetime cumulative doses of anthracyclines, higher dose rates, female sex, longer follow-up, younger age at anthracycline treatment, pre-existing cardiovascular disease, and cardiac irradiation are associated with more severe cardiotoxicity. With deeper understanding of the mechanisms of the adverse cardiac effects and identification of driver mutations causing these effects, personalized cancer therapy to limit cardiotoxic effects can be achieved, such as with the cardioprotectant dexrazoxane.
TL;DR: The epidemiology, mechanisms and risk factors for primary and secondary nonresponse to infliximab in patients with inflammatory bowel disease and data on proactive and reactive therapeutic drug monitoring are examined.
Abstract: Introduction: Primary and secondary non-response to infliximab are common in patients with inflammatory bowel disease and remain a management challenge in clinical practice.Areas covered: This article describes the epidemiology, mechanisms and risk factors for primary and secondary nonresponse to infliximab in patients with inflammatory bowel disease. Data on proactive and reactive therapeutic drug monitoring are examined in this review. An algorithm for evaluation and management of non-response to infliximab is provided. Preventative measures are also discussed. Relevant articles were identified after a literature search using PubMed. Search terms included ‘infliximab’, ‘loss of response’, ‘immunogenicity’, and ‘drug monitoring’. References of identified articles were also reviewed to identify additional references.Expert opinion: A common cause for primary and secondary non-response include inadequate dosing of infliximab; inadequate dosing can be identified through assessment of drug and anti-d...
TL;DR: It is concluded that drugs seem to be well tolerated by the majority of patients with pre-existing, non-cirrhotic chronic liver diseases, however, special care is needed for some therapies, including antiviral therapy in chronic hepatitis B and C and in decompensated liver cirrhosis with impaired drug metabolism.
Abstract: Introduction: Clinicians and practitioners caring for patients with chronic liver disease are often unsure whether drug therapy is a hazard that increases their patient’s risk for drug-induced liver injury (DILI).Areas covered: We searched for reports of drug induced liver injury, both idiosyncratic and intrinsic, in patients with chronic liver disease including non-alcoholic and alcoholic liver disease, and cirrhosis. Reports we analyzed include statin treatment in patients with fatty liver, acetaminophen use in alcoholic fatty liver, antituberculous drugs in patients with tuberculosis and viral hepatitis, antiviral medications in hepatitis and antiretroviral medications in HIV/AIDS. The most challenging cases we found are drug therapy in patients with decompensated liver cirrhosis.Expert opinion: We identified many case reports and case series discussing a potential increased risk of DILI in patients with pre-existing liver disease. However, most of these reports were retrospective and ambiguous...
TL;DR: Overall, as ammonia-scavenging drugs are usually safe and well tolerated among cancer patients, further studies should be instigated to explore the role of these drugs in liver cancer, and it is proposed that ammonia- scaventing drugs might also be used to non-invasively probe liver glutamine metabolism in vivo.
Abstract: Introduction: Ammonia-scavenging drugs, benzoate and phenylacetate (PA)/phenylbutyrate (PB), modulate hepatic nitrogen metabolism mainly by providing alternative pathways for nitrogen disposal.Areas covered: We review the major findings and potential novel applications of ammonia-scavenging drugs, focusing on urea cycle disorders and liver disease.Expert opinion: For over 40 years, ammonia-scavenging drugs have been used in the treatment of urea cycle disorders. Recently, the use of these compounds has been advocated in acute liver failure and cirrhosis for reducing hyperammonemic-induced hepatic encephalopathy. The efficacy and mechanisms underlying the antitumor effects of these ammonia-scavenging drugs in liver cancer are more controversial and are discussed in the review. Overall, as ammonia-scavenging drugs are usually safe and well tolerated among cancer patients, further studies should be instigated to explore the role of these drugs in liver cancer. Considering the relevance of glutamine m...
TL;DR: Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS “Casa Sollievo della Sofferenza”, Italy; Neurodegenerative Disease Unit, University of Bari Aldo Moro, Bari, Italy.
Abstract: Dementia and its most common form, Alzheimer’s disease (AD), are multifactorial incurable syndromes characterized by absence of information on the cause and a dramatic socioeconomical burden. For A...
TL;DR: 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 R UCAM falls short.
Abstract: 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 liter...
TL;DR: An overview of the major epigenetic mechanisms and their effects on the expression of drug metabolizing enzymes and drug transporters, as well as the epigenetic status of drug protein targets affecting therapy response are presented.
Abstract: Introduction: Epigenetics is a rapidly growing field describing heritable alterations in gene expression that do not involve DNA sequence variations. Advances in epigenetics and epigenomics have in...
TL;DR: Clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases is discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted.
Abstract: Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment. Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted. Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.
TL;DR: This manuscript reviews the pharmacogenomics (i.e. the influence of genetics on drug disposition) of triazole antifungal agents related to their CYP-mediated metabolism and summarizes their implications on triazoles efficacy, safety, and tolerability.
Abstract: Triazole antifungal agents are prescribed to treat invasive fungal infections in neutropenic and non-neutropenic patients. These antifungal agents are substrates and inhibitors of cytochrome P450 (CYP). Genetic polymorphisms in CYP2C9, CYP2C19 and CYP3A5 can lead to large population-specific variations in drug efficacy and safety, optimal dosing, or contribute to drug interactions associated with this class. Areas covered: This manuscript reviews the pharmacogenomics (i.e. the influence of genetics on drug disposition) of triazole antifungal agents related to their CYP-mediated metabolism and summarizes their implications on triazole efficacy, safety, and tolerability. A search of English language original research, and scholarly reviews describing the pharmacogenomics of triazole antifungal agents and their impact on drug efficacy, safety, and tolerability published from 1980 to present was undertaken using PubMed. Expert opinion: Currently studies demonstrating the pharmacogenomic influences on itraconazole, posaconazole and isavuconazole are minimal and limited to their inhibitory effects on CYP3A4 in expressors of CYP3A5 variants. Conversely, there are significant pharmacogenomic considerations for voriconazole because it interacts with several polymorphic CYPs, most notably CYP2C19. Pharmacogenomics of CYP2C9 do not appear to effect fluconazole safety and efficacy. However, genetic polymorphisms may influence its drug interactions but this needs further study.
TL;DR: This review provides a comprehensive overview of ADA in rheumatoid arthritis patients treated with anti-TNF immune-biologicals, and explores the concept of therapeutic drug monitoring (TDM) as an effective strategy to improve therapeutic management.
Abstract: Introduction: Genetically engineered monoclonal antibodies and fusion proteins directed against cytokines or their receptors represent a breakthrough in the treatment of various chronic immune-inflammatory diseases.Areas covered: Studies show high remission rates in several diseases, but clinical practice shows a significant percentage of individuals who do not exhibit the desired response. Loss of therapeutic benefit after initial successful response is designated secondary failure. Immune-biological agents are not self-antigens and are therefore potentially immunogenic. Secondary failure is frequently caused by antibodies against immune-biologicals, known as anti-drug antibodies (ADA). ADA that neutralize circulating immune-biologicals and/or promote their clearance can reduce treatment efficacy. Furthermore, ADA can induce adverse events by diverse immunological mechanisms. This review provides a comprehensive overview of ADA in rheumatoid arthritis patients treated with anti-TNF immune-biologi...