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Potential Drug-Drug Interactions of Antiretrovirals and Antimicrobials

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Potential Drug-Drug Interactions of Antiretrovirals and Antimicrobials www.nature.com/scientificreports OPEN Potential drug‑drug interactions of antiretrovirals and antimicrobials detected by three databases Pornpun Vivithanaporn1, Teetat Kongratanapasert2, Bovornpat Suriyapakorn3, Pichayut Songkunlertchai3, Patpicha Mongkonariyawong3, Patanachai K. Limpikirati4 & Phisit Khemawoot1,5* Standard treatment for HIV infection involves a combination of antiretrovirals. Additionally, opportunistic infections in HIV infected patients require further antimicrobial medications that might cause drug‑drug interactions (DDIs). The objective of this study was to to compare the recognition of DDIs between antiretrovirals and antimicrobials by three proprietary databases and evaluate their concordance. 114 items of antiretrovirals and antimicrobials from the National List of Essential Medicines of Thailand 2018 were used in the study. However, 21 items were not recognised by Micromedex, Drugs.com, and Liverpool HIV interactions. Only 93 items were available for the detection of potential DDIs by the three databases. Potential DDIs detected from the three databases included 292 pairs. Liverpool showed the highest number of DDIs with 285 pairs compared with 259 pairs by drugs.com and 133 pairs by Micromedex. Regarding the severity classifcations, Liverpool reported 10% Contraindicated; Micromedex reported 14% contraindicated and 59% major; Drugs. com reported 21% major. The Fleiss’ kappa agreements were fair to poor among the three databases, higher agreement was observed for DDIs classifed as severe. This study highlights the need to harmonize the evaluation and interpretation of DDI risk in order to produce standardized information to support prescribers. Abbreviations AIDS Acquired immunodefciency syndrome ART​ Antiretroviral therapy AUCs Area under curves CYPs Cytochrome P450s DDIs Drug-drug interactions HIV Human immunodefciency virus NLEM National list of essential medicine PD Pharmacodynamics PK Pharmacokinetics UGTs Uridine glucuronosyl transferases Te human immunodefciency virus (HIV) is a lentivirus that causes HIV infection and acquired immunode- fciency syndrome (AIDS)1,2. HIV infection can result in the deterioration of the immune system and lead to opportunistic infections3,4. Terefore, antiretroviral therapy (ART) has been introduced for HIV treatment in order to maintain the immunity of HIV infected patients5,6. Consequently, several drug-drug interactions (DDIs) and adverse events have been reported in the combination of ART7 ,8. Tese DDIs can interfere with antiretroviral efcacy, safety, and patient compliance, and thereby lead to treatment failure9,10. Additionally, the progression of HIV infection can lead to opportunistic infections for which further medications would be prescribed11,12. Te 1Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakarn 10540, Thailand. 2Section for Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 3Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. 4Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. 5Preclinical Pharmacokinetics and Interspecies Scaling for Drug Development Research Unit, Chulalongkorn University, Bangkok, Thailand. *email: [email protected] Scientifc Reports | (2021) 11:6089 | https://doi.org/10.1038/s41598-021-85586-8 1 Vol.:(0123456789) www.nature.com/scientificreports/ Severity Micromedex Drugs.com Liverpool Contraindicated Te drugs are contraindicated for concurrent use N/A Do not coadminister Highly clinically signifcant and includes combinations that Te interaction may be life-threatening and/or require medical Major should be avoided as the risk of the interaction outweighs the N/A intervention to minimize or prevent serious adverse efects beneft Te interaction may result in exacerbation of the patient’s condi- Moderately clinically signifcant and includes combinations that Moderate Potential interaction tion and/or require an alteration in therapy should be avoided and used only under special circumstances Te interaction would have limited clinical efects. Manifesta- Minimally clinically signifcant, i.e. with minimal risk, but an tions may include an increase in the frequency or severity of the Minor alternative drug and steps taken to circumvent the interaction Potential weak interaction side efects but generally would not require a major alteration risk in therapy Table 1. Severity classifcation of potential DDIs determined by the three databases. N/A, not applicable. addition of antimicrobials for opportunistic infections may increase the risk of DDIs13,14. Tere is a challenge in the selection of drug regimens to maximise the efcacy and minimise the toxicity of ART and antimicrobial usage in HIV patients. Recently, electronic DDIs databases were introduced to determine potential DDIs in the prescription of HIV infected patients15,16. Te most popular database for healthcare providers seems to be Micromedex, provided by IBM Corp., USA. Tis database is subject to annual subscription fees, either individually or institutionally. In contrast, Drugs.com is a free online database, favoured by patients to identify potential DDIs, as well as some pharmacists who do not subscribe to the paid database. However, several reports have mentioned that the potential DDIs detected by Micromedex and Drugs.com have low to moderate agreement17,18. Tis has resulted in diferences in the identifcation and management of DDIs. Interestingly, there is a specialised database com- monly used to determine DDIs of HIV medicines in HIV community. Liverpool HIV interaction database focused mainly on HIV drugs was selected into this study in order to determine the ability and agreement of the three electronic databases in detecting potential DDIs of antiretrovirals and antimicrobials in the national list of essential medicines of Tailand (NLEM, 2018). Furthermore, the ability and agreement of the databases was considered in order to fnd the most suitable information for health care providers and HIV patients to optimise drug regimens. Materials and methods Drug selection. All antiretrovirals and antimicrobials were selected from the NLEM of Tailand 201819. Tis study was conducted from 1 to 31 October 2020. Of the 645 total items, only 114 items were antiretro- virals and antimicrobials. However, 21 items were not recognised by one of the three databases, Micromedex (diethylcarbamazine, fusidic acid, protionamide, and sulbactam), Drugs.com (delamanid, diethylcarbamazine, fusidic acid, protionamide, and sulbactam), and Liverpool (artesunate, cefoperazone, cefoxitin, cefuroxime, colistimethate, dicloxacillin, fosfomycin, fusidic acid, micafungin, neomycin, netilmicin, norfoxacin, peramivir, protionamide, roxithromycin, saturated solution of potassium iodide, sulbactam, trimethoprim, and tuberculin purifed protein derivative). Only 93 items were included for the determination of potential DDIs by Microme- dex, Drugs.com, and Liverpool HIV interactions (Fig. 1S and Table 1S). Ethical approval and consent were not required for this study, patient assessment and confdential information were not conducted in this study. Databases. Te Micromedex database used in this study was provided by IBM Corp., USA. Tis database was accessed under the copyright license of Chulalongkorn University (2020). Drugs.com is a free online data- base powered by four independent leading medical-information suppliers: American Society of Health-System Pharmacists, Cerner Multum, Micromedex, and Lexicomp. In total, 93 items of antiretrovirals and antimicrobi- als were inputted into the database on 15 October 2020, in order to determine potential DDIs among antiret- rovirals and antimicrobials. Micromedex reported information on onset, severity, documentation, probable mechanism, summary, literature, clinical management, and references. Drugs.com reported potential DDIs with information on severity, description, management, and references. Te Liverpool HIV interactions reported severity, quality of evidence, summary and description with references. Severity classifcation of potential DDIs determined by the three databases was shown in Table 1. Documentation of DDIs. Micromedex classifes DDIs as excellent documentation when controlled studies have established the existence of the interaction; good documentation is defned as a strong suggestion that the interaction exists, but well-controlled studies are lacking. With fair documentation, the information is poor, but pharmacologic considerations have led clinicians to suspect that the interaction exists, or the documentation is good for a pharmacologically similar drug. Drugs.com did not provide information of documentation in their database. Te Liverpool documentation was reported as quality of evidence. High quality is data obtained from a randomised, controlled interaction trial with clinical or validated surrogate endpoints. Moderate is obtained from crossover or parallel, steady state pharmacokinetics (PK) study with area under curves (AUCs). Low and very low are other kinds of information, e.g., editorial comments, animal studies, case reports without AUCs. Scientifc Reports | (2021) 11:6089 | https://doi.org/10.1038/s41598-021-85586-8 2 Vol:.(1234567890) www.nature.com/scientificreports/ Figure 1. Te severity of the potential DDIs characterised by Micromedex, Drugs.com,
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