Drug Safety Problems Research Articles

When MnSiO3 meets ratiometric fluorescence: A facile, cost-effective ratiometric fluorescent platform based on oxidase-like MnSiO3 nanozyme for versatile Total Antioxidant Capacity (TAC) measurements

The level alterations of antioxidants are highly associated with various oxidative stress-related diseases, food quality and drug safety problems, which enables the reliable and accurate determination of total antioxidant capacity (TAC) become progressively significant. Herein, for the first time, we explored the catalytic effect of MnSiO3 nanozyme with oxidase-like activity towards different fluorescent substrates, and introduced ratiometric fluorescence to MnSiO3-based biosensing. By harnessing MnSiO3-propelled catalytic oxidation of two fluorescent substrates with contrary responses (Scopoletin, SC and o-phenylenediamine, OPD), we constructed a facile, cost-effective ratiometric fluorescent (RF) platform for TAC measurement. In the absence of antioxidants, SC and OPD can be oxidized, and the synergistic effect of fluorescence resonance energy transfer (FRET) and inner-filter-effect (IFE) between SC and oxidized OPD (Ox-OPD) will result in the weak fluorescence of Ox-SC at 465 nm and the strong one of Ox-OPD at 562 nm, respectively. However, the addition of antioxidants will dissociate MnSiO3, generating the recovered high/low fluorescence values of both substrates. Through monitoring the FI465/FI562 changes, the RF analysis of different antioxidants (Cys, AA, GSH) with satisfactory sensitivity is performed and the TAC measurements in diverse real samples (human serums, beverages, and drugs) are successfully accomplished. Moreover, the system demonstrates high selectivity and could compete with the commercial TAC test kits.

EVALUATION OF DERMATOLOGICAL ADVERSE DRUG REACTIONS IN THE OUTPATIENT DEPARTMENT OF DERMATOLOGY AT A TERTIARY CARE HOSPITAL – AN OBSERVATIONAL STUDY

Background: Drugs, no matter how safe and efcacious, come together with the risk of adverse reactions. Of all organs affected by drug reactions, the skin is most frequently involved. To evaluate the dermatological adverse drug Aim and Objectives: reactions in patients attending the Dermatology outpatient department of a tertiary care hospital. An observational, Materials and Methods: cross-sectional study was conducted to evaluate the adverse drug reactions in the Outpatient Department of Dermatology in an Tertiary Care Hospital for a period of 1.5 years. The causality of ADRs was evaluated using WHO-UMC Scale, Naranjo's scale, severity was assessed using Modied Hartwig and Siegel's scale, Preventability was assessed using Schumock and Thorton's criteria. Total 78 Result: drugs were suspected of 67 ADRs. Most common ADR encountered was Maculopapular rash and most common drug causing ADR was found to be antimicrobials. Causality assessment using Naranjo's scale revealed that 59.70% cases were probable, 34.33% cases were possible, 5.97% cases were denite. Causality assessment using WHO-UMC scale revealed that out of total 67 ADR, majority of cases 40 (59.70%) were probable. 19 (28.36%) cases were possible. 8 (11.94%) cases were certain. On preventability assessment 79.1% ADRs were denitely preventable, 20.9 ADRs were probably preventable. Severity assessment concluded that 67.16% were mild, 29.85% moderate, 2.99 % were severe. Proper implementation Conclusion: of ADR monitoring will help to reduce the harmful effects resulting from the use of medicinal products by early detection of drug safety problems in patients.

Audits and inspections of pharmacovigilance systems in Russia

The implementation of pharmacovigilance activities is impossible in isolation from compliance with the quality requirements of medicines and the activities of pharmaceutical and medical organizations throughout the pharmaceutical practice, as well as without access to sales plans, sales results and full relevance of information on drug conditions in all markets and in all cases of application. Properly conducted audit or inspection evaluation of the pharmacovigilance system makes it possible to identify and prevent drug safety problems at all stages of its life cycle.The aim. Development of a risk-based strategy for planning and passing audits and inspections of the pharmacovigilance system for the subsequent creation of effective programs for assessing the pharmacovigilance system on its basis.Material and methods. The study used structurallogical, empirical methods, general logical methods of scientific knowledge, methods of generalization and extrapolation.Results. The plans and results of audits and inspections of pharmacovigilance systems of Russian and foreign pharmaceutical organizations and their pharmacovigilance vendors were analyzed. A risk-based strategy and a checklist for planning internal and external audits of pharmacovigilance systems of Russian pharmaceutical organizations and their vendors for pharmacovigilance have been developed and recommendations for training internal auditors of pharmacovigilance systems and audit teams have been developed for them.Conclusion. Risk assessment indicators adapted for Russia have been developed, according to which Russian pharmaceutical organizations and their pharmacovigilance vendors can assess the likelihood of the risk of priority inclusion in the plan of Russian inspections of pharmacovigilance systems for compliance with the requirements of the good pharmacovigilance practice of the Eurasian Economic Union. Recommendations were prepared for the executive management and pharmacovigilance specialists of Russian pharmaceutical organizations in terms of assessing regulatory risks for the quality system of the pharmacovigilance system, planning and conducting audits; evaluating the relationship of pharmacovigilance with other good practices and with information from the plans and results of the organization as a whole. The indicators adapted for Russia for assessing the compliance of the pharmacovigilance system with the rules of the NPF EAEU are given.

Virtual screening of DrugBank database for hERG blockers using topological Laplacian-assisted AI models

The human ether-a-go-go (hERG) potassium channel (Kv11.1) plays a critical role in mediating cardiac action potential. The blockade of this ion channel can potentially lead fatal disorder and/or long QT syndrome. Many drugs have been withdrawn because of their serious hERG-cardiotoxicity. It is crucial to assess the hERG blockade activity in the early stage of drug discovery. We are particularly interested in the hERG-cardiotoxicity of compounds collected in the DrugBank database considering that many DrugBank compounds have been approved for therapeutic treatments or have high potential to become drugs. Machine learning-based in silico tools offer a rapid and economical platform to virtually screen DrugBank compounds. We design accurate and robust classifiers for blockers/non-blockers and then build regressors to quantitatively analyze the binding potency of the DrugBank compounds on the hERG channel. Molecular sequences are embedded with two natural language processing (NLP) methods, namely, autoencoder and transformer. Complementary three-dimensional (3D) molecular structures are embedded with two advanced mathematical approaches, i.e., topological Laplacians and algebraic graphs. With our state-of-the-art tools, we reveal that 227 out of the 8641 DrugBank compounds are potential hERG blockers, suggesting serious drug safety problems. Our predictions provide guidance for the further experimental interrogation of DrugBank compounds’ hERG-cardiotoxicity.

Characterization of the Complete Chloroplast Genome of Four Species in Callerya.

Callerya reticulata (Bentham) Schot, Callerya dielsiana (Harms) P.K. Loc ex Z. Wei & Pedley, Callerya nitida var. hirsutissima (Z. Wei) X.Y. Zhu, and Callerya nitida (Bentham) R. Geesink, which belongs to the Leguminosae family, are important medicinal plants in China. The genus Callerya includes 26 species, 18 species are distributed in China, and the vine stems of some species are used as traditional medicinal herbs because they have important pharmacological activity. Due to the high similarity of appearance, it is difficult to identify them in the market by appearance alone. Therefore, circulating of Callerya-related materia medica on the market is confusing, sometimes even leading to drug safety problems. It is urgent to develop molecular methods for their identification. To sequence and analyze the complete chloroplast (cp) genomes of C. reticulata, C. dielsiana, C. nitida var. hirsutissima, and C. nitida and to analyze their cp genome differences as a basis for seeking easier DNA barcoding for their identification. After using Illumina high-throughput sequencing and nanopore sequencing to obtain the genome data, some bioinformatics software was used to assembly and analyze the molecular structure of cp genomes. The complete cp genomes of the four species were circular molecules, which ranged from 130 435 to 132 546 bp, and GC contents ranged from 33.89% to 34.89%. Each of them includes a large single-copy region, a small single-copy region, and without large inverted repeat regions. These results suggested that highly variable regions of the four cp genomes would provide useful plastid markers, which could be used as a potential genomic resource to resolve phylogenetic questions and provide a reference for mining specific DNA barcodes of these species. Our study provided highly effective molecular markers for subsequent phylogenetic analysis, species identification, and biogeographic analysis of Callerya.

Multimedication Guidelines: Assessment of the Size of the Target Group for Medication Review and Description of the Frequency of Their Potential Drug Safety Problems with Routine Data

(1) Background: About 10 years ago, several guidelines for the better management of patients with polypharmacy were issued. A central issue is the definition of the target group. The primary aim of this study is therefore to assess the size of the target group, applying the criteria of the German guidelines. A further aim is to describe the frequency of occurrence of medication safety issues for patients of the target group. (2) Methods: The study is based on administrative data of one large statutory health insurer in Germany (n = 9,012,523). (3) Results: The criteria of multimorbidity (at least three chronic diseases) and utilization of five or more concurrent drugs over at least 91 days is fulfilled by 14.1% of the insured patients, or almost 1.3 million persons. About 5% of this multimorbid and poly-medicated population fulfilled at least three of out of five additional occasion-related criteria. Medication safety issues occur frequently: treatment prevalence with potentially inadequate medication, QT-drugs, benzodiazepine or Z-drugs and proton pump inhibitors was 30.4%, 28.9%, 11.1% and 52.4%, respectively. (4) Conclusions: The analysis shows the scope of patients eligible for a structured medication review and demonstrates the relevance for counselling based on the high percentage potentially at risk due to medication therapy safety problems.

A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities.

Impurities in pharmaceuticals of potentially hazardous materials may cause drug safety problems. Macrolide antibiotic preparations include active pharmaceutical ingredients (APIs) and different types of impurities with similar structures, and the amount of these impurities is usually very low and difficult to be separated for toxicity evaluation. Our previous study indicated that hepatotoxicity induced by macrolides was correlated with c-fos overexpression. Here, we report an assessment of macrolide-related liver toxicity by ADMET prediction, molecular docking, structure–toxicity relationship, and experimental verification via detection of the c-fos gene expression in liver cells. The results showed that a rapid assessment model for the prediction of hepatotoxicity of macrolide antibiotics could be established by calculation of the -CDOCKER interaction energy score with the FosB/JunD bZIP domain and then confirmed by the detection of the c-fos gene expression in L02 cells. Telithromycin, a positive compound of liver toxicity, was used to verify the correctness of the model through comparative analysis of liver toxicity in zebrafish and cytotoxicity in L02 cells exposed to telithromycin and azithromycin. The prediction interval (48.1∼53.1) for quantitative hepatotoxicity in the model was calculated from the docking scores of seven macrolide antibiotics commonly used in clinics. We performed the prediction interval to virtual screening of azithromycin impurities with high hepatotoxicity and then experimentally confirmed by liver toxicity in zebrafish and c-fos gene expression. Simultaneously, we found the hepatotoxicity of azithromycin impurities may be related to the charge of nitrogen (N) atoms on the side chain group at the C5 position via structure–toxicity relationship of azithromycin impurities with different structures. This study provides a theoretical basis for improvement of the quality of macrolide antibiotics.

Outcomes of activated prothrombin complex concentrate for direct Xa inhibitor bleeding

Bleeding due to oral anticoagulant therapy is recognized as a high priority drug safety problem [ [1] FDA Adverse Events Reporting System (FAERS)Latest Quarterly Data Files (2017) Food and Drug Administration Web Site. 2021 Google Scholar ]. As the use of direct Xa inhibitors continues to expand, the management of bleeding is an important issue. Andexanet, a modified human factor Xa decoy reversal agent for apixaban or rivaroxaban associated bleeding, is available in some countries however concerns with its use have been expressed [ [2] Peled H. Dau N.Q. Lau H. Key points to consider when evaluating andexxa for formulary addition. Neurocrit. Care. 2020; 33: 20-24 Crossref PubMed Scopus (7) Google Scholar ]. Four factor prothrombin complex concentrate (4FPCC) is an alternative reversal agent which has been used off-label for direct Xa inhibitor bleeding [ 3 Steffel J. et al. The 2018 european heart rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur. Heart J. 2018; 39: 1330-1393 Crossref PubMed Scopus (1060) Google Scholar , 4 Witt D.M. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018; 2: 3257-3291 Crossref PubMed Scopus (188) Google Scholar ]. Four factor PCC is available either as an activated or non-activated product. Limited clinical data exist evaluating activated 4FPCC, FEIBA [anti-inhibitor coagulant complex®, Baxalta US Inc., Lexington MA, USA] as a reversal agent [ 5 Engelbart J.M. et al. Safety and effectiveness of factor eight inhibitor bypassing activity for direct oral anticoagulant-related hemorrhage reversal. Am. J. Emerg. Med. 2019; 37: 214-219 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar , 6 Mao G. et al. Factor eight inhibitor bypassing agent (FEIBA) for reversal of target-specific oral anticoagulants in life-threatening intracranial bleeding. J. Emerg. Med. 2017; 52: 731-737 Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar ]. As andexanet is not on formulary, the reversal protocol at our institution recommended the use of activated 4FPCC 25–50 IU/kg for direct Xa inhibitor bleeding for situations where reversal is desired. Our goal was to assess the patient characteristics, management and outcomes of activated 4FPCC for reversal of apixaban or rivaroxaban acute bleeding events.

SumRe: Design and Evaluation of a Gist‐based Summary Visualization for Incident Reports Triage

AbstractIncident report triage is a common endeavor in many industry sectors, often coupled with serious public safety implications. For example, at the US Food and Drug Administration (FDA), analysts triage an influx of incident reports to identify previously undiscovered drug safety problems. However, these analysts currently conduct this critical yet error‐prone incident report triage using a generic table‐based interface, with no formal support. Visualization design, task‐characterization methodologies, and evaluation models offer several possibilities for better supporting triage workflows, including those dealing with drug safety and beyond. In this work, we aim to elevate the work of triage through a task‐abstraction activity with FDA analysts. Second, we design an alternative gist‐based summary of text documents used in triage (SumRe). Third, we conduct a crowdsourced evaluation of SumRe with medical experts. Results of the crowdsourced study with medical experts (n = 20) suggest that SumRe better supports accuracy in understanding the gist of a given report, and in identifying important reports for followup activities. We discuss implications of these results, including design considerations for triage workflows beyond the drug domain, as well as methodologies for comparing visualization‐enabled text summaries.

A pharmacovigilance study in patients of chronic non-infective respiratory diseases attending outpatient department of pulmonary medicine in a tertiary care teaching hospital

Background: Adverse drug reactions (ADR) are the known dangers of any medicinal therapy. They are not only responsible for increasing the mortality and morbidity but also for multiplying the health care expenditure. It is important to monitor the adverse effects of the drugs in the patients on treatment for chronic non-infective respiratory diseases attending OPD of pulmonary medicine in a tertiary care teaching hospitalMethods: The study was single-centric, non-randomized and observational hospital-based study which was carried out for a period of 1 and a half years in JJ Hospital. The patients who were included in the study suffered from either of the 4 diseases-Chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis or interstitial lung diseases (ILD). Data were analyzed by using Microsoft excel sheet. Based on the outcome of modified Hartwig and Siegel severity assessment scale, ADRs were grouped into various severity categories.Results: One hundred and thirty-two number of ADRs were seen in 69 out of 352 patients (19.6 %) of the study population. The occurrence of ADR was found slightly higher in males i.e., 53.62% as compared to females i.e., 46.38%. The patients who were on treatment for ILD showed highest percentage of ADRs i.e., 57.89% which is followed by bronchiectasis (17.39%), COPD (16.17%) and lastly asthma (10.26%). The ADRs belonging to GIT system were highest in number i.e., 80. The most frequently occurring ADR in the study was palpitation which occurred in 14 cases i.e., 20.29%. Out of 132 ADRs observed, 96 i.e., 72.73% belonged to the mild category and 36 ADRs i.e., 27.27% belonged to the moderate category. Not a single severe ADR was found in the study.Conclusions: It was found that 19.6% of the patient population suffered from ADRs, which is a considerable number. It is essential that health care professionals should support ADR monitoring process for the safety of the medicinal product. Proper implementation of ADR monitoring will help to reduce the harmful effects by early detection of drug safety problems in patients, assessing the risk-benefit in an individual and the population, improving the selection, rational use of drugs through the provision of timely warning to healthcare professionals.

Utilizing drug-target-event relationships to unveil safety patterns in pharmacovigilance

ABSTRACT Introduction Signal detection is the most pivotal activity of signal management to guarantee that drugs maintain a positive risk-benefit ratio during their lifetime on the market. Signal detection is based on the systematic evaluation of available data sources, which have recently been extended in order to improve timely and comprehensive signal detection of drug safety problems. Areas covered In recent years, attempts have been made to incorporate pharmacological data for the prediction of safety signals. Previous studies have shown that data on the pharmacological targets of drugs are predictive of post-marketing adverse events. However, current approaches limit such predictions to adverse events expected from the interaction of a drug with the main pharmacological target and do not take off-target interactions into consideration. Expert opinion The authors propose the application of predictive modeling techniques utilizing pharmacological data from public databases for predicting drug-target-event relationships deriving from main- and off-target binding and from which potential safety signals can be deduced. Additionally, they provide an operative procedure for the identification of clinically relevant subgroups for predicted safety signals.

A Review of Drug Side Effect Identification Methods.

Drug side effects have become an important indicator for evaluating the safety of drugs. There are two main factors in the frequent occurrence of drug safety problems; on the one hand, the clinical understanding of drug side effects is insufficient, leading to frequent adverse drug reactions, while on the other hand, due to the long-term period and complexity of clinical trials, side effects of approved drugs on the market cannot be reported in a timely manner. Therefore, many researchers have focused on developing methods to identify drug side effects. In this review, we summarize the methods of identifying drug side effects and common databases in this field. We classified methods of identifying side effects into four categories: biological experimental, machine learning, text mining and network methods. We point out the key points of each kind of method. In addition, we also explain the advantages and disadvantages of each method. Finally, we propose future research directions.

Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study.

Oral factor Xa (fXa) inhibitor-related bleeding is a concerning drug safety problem. There is considerable controversy surrounding available reversal strategies. The recently approved reversal agent andexanet alfa has limited data, an unclear safety profile, and imparts a substantial financial burden. This has led to the off-label use of four-factor prothrombin complex concentrates (4F-PCC) for this indication. This study aimed to assess the safety and efficacy of 4F-PCC for the management of major bleeding related to oral fXa inhibitors. This observational, retrospective study included adult patients admitted from 2014 to 2018 who received 4F-PCC (Kcentra®) for fXa inhibitor-related major bleeding. Efficacy was assessed using criteria described by Sarode et al. Secondary outcomes included the incidence of thromboembolism, mortality, and a cost analysis comparing 4F-PCC to andexanet alfa for reversal of oral fXa inhibitors. Thirty-one patients received 4F-PCC for major bleeding associated with apixaban (55%) or rivaroxaban (45%). Intracranial hemorrhage (58%) and pericardial effusion (16%) accounted for the majority of bleeding events. Most patients received a single weight-based 4F-PCC dose of 25 units/kg (38.7%) or 50 units/kg (51.6%). Effective hemostasis was achieved in 80.6% of patients. Five patients (16%) died due to acute bleeding and no thromboembolic events were observed. Administration of 4F-PCC was effective for most patients requiring emergent reversal of anticoagulation with apixaban or rivaroxaban and was associated with a low risk of thromboembolic events. Considerable cost differences limit the use of andexanet alfa and may warrant further study of 4F-PCC for fXa inhibitor reversal.

A systematic review of phenytoin intoxication induced by compound phenytoin sodium, ephedrine hydrochloride and theophylline tablets in China.

Objective:In this study, we aimed to review the literature on phenytoin intoxication induced by compound phenytoin sodium, ephedrine hydrochloride and theophylline tablets (CPEHTT).Method:A literature search was performed in the following databases: WANFANG DATA, HowNet, National Library Reference and Consultation Alliance, Full-text Database of Foreign Medical Journals, PubMed and Ovid. The search terms were “Compound Phenytoin Sodium, ephedrine Hydrochloride and Theophylline Tablets,” and “poisoning,” or “toxicity,” in Chinese and in English.Result:Ten articles including 104 patients with CPEHTT intoxication were identified. The ages of the patients ranged from 52 to 82 years. Sixty-seven patients were male and thirty-seven patients were female (the male/female ratio, approximately 2:1). The most common clinical manifestations were dizziness (85%) and ataxia (85%), followed by limb weakness (65%), diplopia (25%), binocular horizontal nystagmus (24%), limb numbness (13%), nausea and vomiting (12%), somnolence (10%), tremor and high muscle tension (7%), lag in response (5%), dysarthria (6%), choking cough (2%), auditory hallucination and visual fantasy (1%), and involuntary movement (1%). All patients had chronic lung disease, and the most common disease was chronic bronchitis. The dosage ranged 4 to 15 tablets per day with medication duration of more than 1 year for most patients.Conclusion:The CPEHTT intoxication caused by phenytoin toxicity represents a drug safety problem in China. The common clinical manifestations, serum phenytoin concentrations, and associated factors of CPEHTT intoxication are important for diagnosis and prevention. These findings may help guide clinicians to correctly attend to the use of CPEHTT and avoid its toxicity.

Regulatory Gaps in Drug Compounding: Implications for Patient Safety, Innovation, and Fraud

Drug compounding is the practice of mixing, combining, or altering drug ingredients to create a product that meets the medical needs of a patient whose needs cannot otherwise be met with commercially-available products. Although drug compounding fills a critical need for many patients, it has also given rise to significant drug safety concerns, fraud, and anticompetitive practices. Every year, many patients experience harmful side effects and even death from compounded drugs that are contaminated or made in excessive potency because of pharmacist error. The ability of pharmacies to make and dispense drugs outside of the typical channels has also given rise to extensive fraud. In addition, some rogue pharmacies earn significant profits by mass-producing compounded drugs that are essentially copies of commercially-available drugs. Many of the drug safety problems, fraudulent practices, and anti-competitive behaviors are facilitated by regulatory gaps in the oversight of drug compounding. Traditional drug manufacturers must prove that their drugs are safe and effective and manufactured in accordance with current good manufacturing practices (CGMPs) in order to obtain FDA approval. In contrast, compounders need not obtain FDA approval for their drugs before selling them, and most compounders do not have to produce drugs in accordance with CGMPs. Moreover, traditional drug manufacturing facilities are subject to routine inspection by the FDA to ensure they are in compliance with CGMPs and that there are no other safety or quality concerns. In contrast, most compounders are not primarily overseen by the FDA but by state boards of pharmacy that are less consistent in their oversight — fewer than half of the states even conduct routine inspections of compounding pharmacies. Finally, whereas traditional manufacturers are required to report adverse events involving their drugs to the FDA, most compounders do not have to report adverse events to either the FDA or state regulatory authorities. This Article explains the regulatory gaps in drug compounding that give rise to drug safety problems, fraud, and anti-competitive behavior and proposes various measures that could be taken to close the gaps in order to protect patients, payors, and innovation.

Risk perceptions and risk attitudes among Chinese consumers: the toxic capsule crisis

The toxic capsule crisis (TCC) shocked China in 2012, and seriously harmed consumer confidence. Based on a firsthand survey in 12 provinces with 850 observations, this paper examines Chinese consumers’ risk perceptions and risk attitudes about drugs after the TCC. The empirical results suggest that Chinese consumers’ risk perceptions (attributed likelihood of a drug safety accident occurrence) and risk attitudes (measured as level of concern about drug labeling) are weakly negatively correlated, but that risk perceptions are positively correlated with consumer concern about drug safety problems in general. Risk perception was higher among male consumers and those from rural areas, reporting a religious faith, of higher education, and with a family member who has experienced problems caused by drug safety problems. Those reporting a higher level of concern about drug safety issues, with a higher level of understanding of TCC, who reported less frequent physical examinations, and who searched for information after the TCC also had a higher level of risk perception. Being or having a family member who engaged in the health industry and being more satisfied with the government response to the TCC decreased risk perception. Regarding risk attitude, older consumers, those with a higher level of education and with a self-reported religious faith, and those less prepared including those who did not purchase health insurance, do not have health exams as frequently, and who do not take measures of protection and isolation when ill are more concerned about drug labeling information.

Identification of Drug-Drug Interactions In Vitro: A Case Study Evaluating the Effects of Sofosbuvir and Amiodarone on hiPSC-Derived Cardiomyocytes.

Drug-drug interactions pose a difficult drug safety problem, given the increasing number of individuals taking multiple medications and the relative complexity of assessing the potential for interactions. For example, sofosbuvir-based drug treatments have significantly advanced care for hepatitis C virus-infected patients, yet recent reports suggest interactions with amiodarone may cause severe symptomatic bradycardia and thus limit an otherwise extremely effective treatment. Here, we evaluated the ability of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to recapitulate the interaction between sofosbuvir and amiodarone in vitro, and more generally assessed the feasibility of hiPSC-CMs as a model system for drug-drug interactions. Sofosbuvir alone had negligible effects on cardiomyocyte electrophysiology, whereas the sofosbuvir-amiodarone combination produced dose-dependent effects beyond that of amiodarone alone. By comparison, GS-331007, the primary circulating metabolite of sofosbuvir, had no effect alone or in combination with amiodarone. Further mechanistic studies revealed that the sofosbuvir-amiodarone combination disrupted intracellular calcium (Ca2+) handling and cellular electrophysiology at pharmacologically relevant concentrations, and mechanical activity at supra-pharmacological (30x Cmax) concentrations. These effects were independent of the common mechanisms of direct ion channel block and P-glycoprotein activity. These results support hiPSC-CMs as a comprehensive, yet scalable model system for the identification and evaluation of cardioactive pharmacodynamic drug-drug interactions.

Abstract 3916: A “moneyball” approach to predicting clinical trial toxicity events

Abstract Over the past decade, significant strides have been made in the management and treatment of various diseases. Despite this progress, clinical attrition rates have continued to substantially rise. Clinical trials can fail for a variety of reasons, ranging from design issues to drug efficacy and safety problems. Drug-likeness approaches, as first proposed by Lipinski almost two decades ago, have become a key tool for the pre-selection of compounds that are likely to have manageable toxicity in clinical studies. However all these methods consider molecular properties of the drug itself alone. In general, these approaches struggle to simultaneously well-characterize the properties of both FDA approved drugs (which we term the sensitivity) and drugs that fail clinical trials (specificity). We introduce an approach that integrates chemical properties of a compound, along with that of its targets, to provide a new quantitative measure that helps predict whether drugs in clinical trials will fail for toxicity reasons. When trained on failed clinical trials and FDA approved drugs, this method performs at a high accuracy, specificity and sensitivity (∼0.75), as well as high area under the ROC curve (>0.80). In comparison, none of the drug-likeness approaches were able to successfully maintain both high sensitivity and specificity. A feature analysis of the model indicates that it is critical to consider both structural properties and properties of the drug target, with the target's network connectivity and liver toxicity as two important features. The approach was further evaluated by testing the predictions of the trained model on an established independent dataset. We found that our method was able to significantly distinguish a representative set of bioavailable drugs from a representative set of toxic drugs (D = 0.2133, p<2.2e-16, Kolmogorov-Smirnov test). Additionally, we found that the measure is strongly correlated with severe toxicity events, such as pleural effusion (ρ = −0.9792) and neutropenia (ρ = −0.9613). Altogether, our method provides a novel, broadly applicable strategy that is able to identify drugs likely to possess manageable toxicity in clinical trials. Citation Format: Kaitlyn Gayvert, Neel Madukhar, Olivier Elemento. A “moneyball” approach to predicting clinical trial toxicity events. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3916.

Pharmacovigilance Practice: The Current Challenges and the Gaps in the Medical Students' Curriculum

Adverse drug reaction is defined by the WHO as a response to a medicinal product which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, therapy of disease or for the modification of physiologic function. The term Pharmacovigilance was coined by a French group of pharmacologist and toxicologist in the 1970s, which implied strategy promoting detection and assessment of side effects and adverse drug reaction. The first endeavor made to resolve the problem of drug safety was announced in 1961 promptly after the disaster caused by thalidomide treatment in pregnant women. The World Health Organization center for adverse drug reaction monitoring is known as the Uppsala Monitoring Centre. It is an International establishment with the responsibility of coordinating the program based on an agreement made in 1978. The major challenges of Pharmacovigilance program are underreporting, and the best solution is to resolve the problem from the grassroots. This claim could be justified as the outcome of previous knowledge, attitude and practice studies on adverse drug reactions and Pharmacovigilance among medical students was inadequate. Also, the curriculum of teaching and training of medical students was insufficient. The aim of this review was to discuss the current challenges facing adverse drug reactions reporting system and to highlight the gap left in the training of medical students.

Abstract B142: A “moneyball” approach to predicting clinical trial failures and successes

Abstract Over the past decade, significant strides have been made in the management and treatment of various diseases. Despite this progress, drug attrition rates due to clinical trial failure have continued to substantially rise. Clinical trials can fail for various reasons, ranging from design issues to drug efficacy and safety problems. Drug-likeness approaches, as first proposed by Lipinski almost two decades ago, have become a key tool for the pre-selection of compounds that are likely to have manageable toxicity in clinical studies. However all these methods consider molecular properties of the drug itself alone. In general, these approaches struggle to simultaneously well-characterize the properties of both FDA approved drugs (sensitivity) (and drugs that fail clinical trials (specificity). We introduce a novel data-driven approach (PrOCTOR) that integrates chemical properties of a compound, along with that of its targets, to provide a new measure, the PrOCTOR score, that helps predict whether drugs in clinical trials will fail for toxicity reasons. When trained on failed Phase I clinical trials and FDA approved drugs, the PrOCTOR score performs at a high accuracy, specificity and sensitivity (∼0.75), as well as high area under the ROC curve (>0.80). In comparison, none of the drug-likeness approaches were able to successfully maintain both high sensitivity and specificity. Robust feature analysis of the model indicates that it is critical to consider properties of the drug target, with the target's network connectivity and liver toxicity as two of the most important features. The approach was further evaluated by testing the predictions of the trained model on an established independent dataset. We found that our method was able to significantly distinguish a representative set of bioavailable drugs from a representative set of toxic drugs (D = 0.2133, p<2.2e-16, Kolmogorov-Smirnov test). Additionally, we found that the measure is strongly correlated with severe toxicity events, such as pleural effusion (ρ = −0.9792) and neutropenia (ρ = −0.9613). Altogether, our method provides a novel, data-driven and broadly applicable strategy that is able to identify drugs likely to possess manageable toxicity in clinical trials. Citation Format: Kaitlyn Gayvert, Neel Madhukar, Olivier Elemento. A “moneyball” approach to predicting clinical trial failures and successes. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B142.