A descriptive analysis of drug related problems identified when prescribing the COVID-19 antiviral drug Paxlovid®

A descriptive analysis of drug related problems identified when prescribing the COVID-19 antiviral drug Paxlovid® | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A descriptive analysis of drug related problems identified when prescribing the COVID-19 antiviral drug Paxlovid® Alina Stoiber, Gwen Gray, Gudrun Sailer, Wolfgang Huf, Antonella Tonna This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4973191/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Dec, 2024 Read the published version in International Journal of Clinical Pharmacy → Version 1 posted 5 You are reading this latest preprint version Abstract Background Paxlovid® is the only licensed oral COVID − 19 antiviral containing nirmatrelvir and ritonavir. Ritonavir is a potent inhibitor of cytochrome P450 enzymes resulting in clinically significant drug-drug interactions (DDIs). Aim To describe the frequency, type, and severity of detected drug related problems (DRPs) with Paxlovid® Method This study involved a retrospective, quantitative data analysis. All patients prescribed Paxlovid® in a public hospital in Vienna, were included. Data was collected from the patients’ records and recorded on a customised and piloted data collection form. Any DRPs were also noted. The severity of DDIs was classified using an established checker tool. Results 122 of 140 (87.1%) patients required interventions to prevent DRPs; 63.6% of cases required intervention by the pharmacist at dispensing. The most common DRPs were DDIs (57.1%). In 24.3% of cases both renal impairment and DDIs were noted. 313 DDIs were recorded in 114 patients; in 24 patients, the interactions recorded were severe. In 3 patients (2.1%), Paxlovid® was prescribed despite being contraindicated due to severe renal impairment requiring pharmacist intervention. Conclusion This study demonstrated that numerous DRPs involving Paxlovid® were identified by the pharmacist following prescribing. Pharmacists’ involvement in prescribing highly interacting drugs such as Paxlovid® is beneficial to enhance patient safety. Figures Figure 1 Impact on Practice Pharmacist screening for drug related problems at the point of dispensing is likely to increase patient safety and mitigate risk associated with high-risk drugs. The study confirms that a strong focus needs to be placed on reviewing the patients´ renal function and adjusting dosing accordingly both as part of the prescribing and screening processes. Introduction The development of vaccines was a significant milestone in the fight against the coronavirus (COVID-19). However, immunosuppressed patients do not respond adequately to the vaccine and require additional protection [1]. Various treatments preventing the progression of COVID-19 [2] require intravenous administration making accessibility challenging. Paxlovid®, a combination of nirmatrelvir and ritonavir, is the only preparation available orally to treat COVID-19 that is licensed in Europe enhancing accessibility for outpatients. Use of Paxlovid® maybe challenging due to ritonavir's potent inhibition of Cytochrome P450 enzymes, leading to numerous drug interactions [3-6]. Additionally, nirmatrelvir, when administered in combination with ritonavir, is renally excreted unchanged requiring dose adjustments in patients with moderate renal impairment (eGFR ≤ 60 ml/min) [3]. In patients with severe renal impairment (eGFR < 30 ml/min), Paxlovid® is contraindicated [3,7]. Therefore, a comprehensive medication review is imperative for every patient prescribed Paxlovid®. In view of the above, pharmacists in some countries such as the US and Canada have been authorized to prescribe and dispense Paxlovid® to enhance patient safety [8,9]. In Austria, only doctors can prescribe Paxlovid® [10]. Nevertheless, pharmacists can play an important role in ensuring patient safety by conducting medication reviews and providing support during the prescribing process. A pharmaceutical service involving medication reviews of all patients on Paxlovid® was introduced in an Austrian public hospital (Figure 1). Figure 1 placed here Aim The aim was to describe the frequency, type, and severity of detected DRPs with Paxlovid® Ethics approval The study was approved by the Ethics Committees of Robert Gordon University (1st Feb 2023/S331) and the City of Vienna (10th Mar 2023/EK23-028-VK). Method A retrospective, single centre, descriptive data analysis was performed in a 750-bed-capacity public hospital in Vienna, Austria. Inpatients who tested positive for COVID-19 and prescribed Paxlovid® were included and identified through the hospital software system. Demographic details of patients prescribed Paxlovid® between September 2022 to March 2023 were collected and recorded in a customized and anonymized Data Collection Tool (DCT) [See Appendix I]. The DCT developed was piloted using 10 patient records where the data was collected by two clinical pharmacists (AS, RC) and independently checked for consistency by a third (GS). Cohen´s kappa statistic was used to check for inter-rater reliability [ 11 ] which was 100% for every component. Other information collected included any DDIs identified together with the degree of severity of the interaction as per University of Liverpool interaction checker [ 12 , 13 ]. Descriptive statistics were generated and supported by Excel. Results Participant characteristics 140 patients were prescribed Paxlovid® during the data collection period with 58 males and a median age of 75.2 years (range 24 - 101 years). All had a medication review performed by a trained clinical pharmacist. The median number of concomitantly used drugs per patient was 9.8 (ranging 1 - 23) with an average of 2.2 (± 1.8) interactions with Paxlovid® per patient. Table 1 summarises the characteristics of patients included. Table 1 placed here Analysis of all patients prescribed Paxlovid® during the study period indicated that in 12.9% (18 of 140 patients) of patients, no drug related problem (DRP) was identified and therefore no intervention was required. In the other 87.1% (122 of 140) of cases DRPs were identified. In 33 cases these actions were performed by the prescribers at prescribing stage. In 89 (63.6%) cases the required action was not identified at the point of prescribing but during the pharmaceutical medication analysis after Paxlovid® was ordered in the pharmacy. The nature of the DRPs identified were as follows: in 5.7% (n=8) of patients, a dose reduction of Paxlovid® was recommended or Paxlovid® contraindicated due to the patient´s renal function; in 57.1% (n=80) drug-drug interactions (DDIs) were identified. In 24.3% (n=34) of all cases renal impairment and DDIs were noted. Drug-drug interactions and required interventions Multiple interactions were identified in individuals due to polypharmacy resulting in a total of 313 DDIs identified in 114 patients (81.4%). Sixty-eight drugs were accountable for these DDIs (see Table 2), with nine drugs having the potential to cause severe interactions with Paxlovid® (red). In three cases where Paxlovid® was contraindicated due to severe renal impairment no extended medication review was conducted. In 24 out of 114 patients where interactions were identified at least one was severe (red) interaction, in 86 patients, at least one possible (orange) interaction was identified, while in 4 patients at least one mild (yellow) interaction was identified. For each of the 313 identified interactions an intervention was recommended based on guidance available in the Liverpool interaction checker. These included the prescribing of a different COVID-19 medication (n = 5; 1.6%), the temporary withdrawal of the patient’s regular medication [118 interactions (37.7 %)] during Paxlovid® administration, dose adjustment to the regular medication [33 interactions (10.5 %)] and closer patient monitoring including blood pressure, ECG or drug monitoring [109 interactions (34.8 %)]. Table 2 placed here Paxlovid® in patients with decreased renal function 39 out of the 140 screened patients (27.9%) had moderate renal impairment (30 ≤ eGFR < 60 ml/min) requiring a dose reduction of Paxlovid®. This had been considered in 14 cases by the prescribing physician but was highlighted and recommended by the designated clinical pharmacists in the other 25 cases. Three out of 140 (2.1%) had severe renal impairment (eGFR < 30 ml/min) with Paxlovid® prescribed despite the contraindication with an alternative recommended by the pharmacist during the screening process. Discussion Statement of key findings This study shows that interventions were still required in most of the prescriptions for Paxlovid® screened by the pharmacists, even though screening had routinely been conducted at the point of prescribing. These findings confirm those in the literature which also suggest that collaboration of medical doctors and pharmacists and involvement of clinical pharmacists in screening can lead to reduced rates of DRPs in hospital as well as in community settings [ 14 – 16 ]. Strengths and weaknesses The strength of the study lies in the way data was obtained with data concerning DDIs collected and rated separately for each drug. The fact that pharmacists in Austria are independent from prescribing decisions ensures objectivity during the screening process. Limitations of this study include the study’s small sample size and the monocentric setting limiting the generalizability of the results and the lack of comparable published data since the drug is relatively new. Interpretation The results of our study are highly relevant in the context of a US retrospective, observational cohort study that concluded that approximately one third of patients treated with ritonavir-containing COVID therapy may be at risk of major or contraindicated drug-drug interactions requiring a skilled assessment of possible DDIs before prescribing and dispensing the drug [ 17 ]. This is particularly relevant in elderly, patients with comorbidities and women [ 17 ]. A retrospective review of a pharmacist-led dispensing service conducted in a US community pharmacy setting highlighted the ability of pharmacists to identify and address DRPs involving oral COVID-19 drugs [ 18 ] with one or more significant DRPs identified in 78% of Paxlovid® prescriptions at the point of dispensing [ 18 ]. Most interventions identified involved DDIs with HMG-CoA reductase inhibitors, calcium channel blockers, fluticasone nasal sprays, benzodiazepines, antiplatelet therapies and alpha-blockers [ 18 ]. A study reporting a pharmacy service in an ambulatory care setting identified HMG-CoA reductase inhibitors, Tamsulosin, Trazodone, Amlodipine and Apixaban among the top 10 most frequent drugs to interact with Paxlovid® [ 19 ]. Apart from fluticasone nasal spray, the drugs identified are like those in our study. The average number of identified possible DDIs with Paxlovid ® per patient was slightly higher in our study (2.2 ± 1.8) compared to that published by Portman and Scolese (1.7 ± 1.3) [ 19 ]. The reason for the deviation is potentially since all possible DDIs were considered in our study while Portman and Scolese only included ´significant drug interactions´ [ 19 ]. Nevertheless, a similar number of patients were found to have at least one significant interaction with Paxlovid® (80% of patients compared to 81.4% in our study) [ 19 ]. Evidence indicates that physicians do not always sufficiently take the patient´s renal function into account when prescribing [ 14 , 20 – 22 ]. For example, a study by Hassan et al showed that the involvement of a pharmacist on ward rounds led to increased consideration of relevant dose adjustments due to impaired renal function [ 20 ]. Similarly, in a retrospective review by Kieck et al, dose reduction of Paxlovid® in patients with decreased renal function was not considered by the prescriber but only subsequently implemented by the pharmacists [ 18 ]. Likewise, in our study, patients’ doses of Paxlovid® were not reduced in response to the patient’s renal function, but adjusted only following recommendations by the pharmacists and after the prescription had been issued and during the screening process. Conclusion In conclusion, it is recommended that pharmacists are routinely involved in the process of prescribing highly interactive drugs such as Paxlovid®. Considering the final draft guidance from the National Institute for Health and Care Excellence (NICE) suggesting an extension of the list of categories of patients who test positive for COVID-19 and who should be considered for Paxlovid®, there is a likelihood of an increased use of the drug [ 24 ]. Results are even more significant in view of draft legislation presented by the Austrian Parliament suggesting the legalisation of certain changes in a patient`s medication by hospital pharmacists following medical instruction [ 23 ]. Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Conflict of Interests The authors declare that they have no conflict of interest. References Center for Disease Control and Prevention (CDC). People with Certain Medical Conditions . CDC. 2023. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Accessed 5 Feb 2023. Center for Disease Control and Prevention (CDC). COVID-19 Treatments and Medications. CDC. 2024. https://www.cdc.gov/coronavirus/2019-ncov/your-health/treatments-for-severe-illness.html. Accessed 12 Feb 2024. Electronic Medicines Compendium (EMC). Paxlovid 150 mg/100 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (emc). EMC. 2022. https://www.medicines.org.uk/emc/product/13145/smpc. Accessed 5 Feb 2023. Liverpool Interaction Group. Evaluating the drug-drug interaction risk of COVID-19 therapies (licensed or under clinical investigation). University of Liverpool. 2022. www.covid19-druginteractions.org/prescribing_resources/methods-metabolism. Accessed 5 Feb 2023. Hull MW, Montaner JSG. Ritonavir-boosted protease inhibitors in HIV therapy. Annals of Medicine . 2011;43(5):375–388. https://doi.org/10.3109/07853890.2011.572905 World Health Organization (WHO). WHO model list of essential medicines - 22nd list, 2021 . WHO. 2021. https://www.who.int/publications-detail-redirect/WHO-MHP-HPS-EML-2021.02. Accessed 5 Feb 2023. National Health Service (NHS). Chronic kidney disease - Diagnosis - NHS . NHS. 2019. https://www.nhs.uk/conditions/kidney-disease/diagnosis/. Accessed 14 Mar 2023. Tanne JH. Covid-19: FDA authorises pharmacists to prescribe Paxlovid. BMJ . 2022;378. https://doi.org/10.1136/bmj.o1695 Traynor K. Québec authorizes pharmacists to prescribe Paxlovid . American Journal of Health-System Pharmacy. 2022;79(14):1126–1127. https://doi.org/10.1093/ajhp/zxac163 Bundesministerium für Finanzen. RIS - Rezeptpflichtgesetz - Bundesrecht konsolidiert, Fassung vom 22.03.2023 . Bundesministerium für Finanzen. 2023.https://www.ris.bka.gv.at/GeltendeFassung.wxe?Abfrage=Bundesnormen&Gesetzesnummer=10010351. Accessed 22 Mar 2023. McHugh M. Interrater reliability: the kappa statistic . Biochemia Medica, 2012;22(3):276–282. The University of Liverpool. Liverpool COVID-19 Interactions . The University of Liverpool. 2023. https://www.covid19-druginteractions.org/checker#. Accessed 14 Feb 2023. Liverpool Interaction Group. Interactions with Outpatient Medicines & Nirmatrelvir/ritonavir (NMV/r). University of Liverpool. 2023. www.covid19-druginteractions.org/prescribing_resources/paxlovid-outpatient-medicines. Accessed 15 Feb 2024. Kucukarslan SN, Peters M, Mlynarek M et al. Pharmacists on rounding teams reduce preventable adverse drug events in hospital general medicine units. Arch Intern Med . 2003;163(17):2014-2018. https://doi.org/10.1001/archinte.163.17.2014 Roblek T, Deticek A, Leskovar B et al. Clinical-pharmacist intervention reduces clinically relevant drug–drug interactions in patients with heart failure: A randomized, double-blind, controlled trial. International Journal of Cardiology . 2016;203:647-652. https://doi.org/10.1016/j.ijcard.2015.10.206 Tasaka Y, Tanaka A, Yasunaga A et al. Potential drug-related problems detected by routine pharmaceutical interventions: safety and economic contributions made by hospital pharmacists in Japan. Journal of Pharmaceutical Health Care and Sciences 4 . 2018;33. https://doi.org/10.1186/s40780-018-0125-z Igho-Osagie E, Puenpatom A, Williams MG et al. Prevalence of potential drug-drug interactions with ritonavir-containing COVID-19 therapy. J Manag Care Spec Pharm . 2023;29(5):509-518. https://doi.org/10.18553/jmcp.2023.22366 Kieck D, Mahalick L and Vo TT. Medication-Related Problems Identified and Addressed by Pharmacists Dispensing COVID-19 Antivirals at a Community Pharmacy. Pharmacy . 2023; 11(3):87. https://doi.org/10.3390/pharmacy11030087 Portman D.B. and Scolese C.J. Facilitating oral COVID-19 therapy utilization through a pharmacy consult service. JAPhA . 2023; 63(4):1237-1241. https://doi.org/10.1016/j.japh.2023.04.010 Hassan Y, Al-Ramahi RJ, Aziz NA et al. Impact of a renal drug dosing service on dose adjustment in hospitalized patients with chronic kidney disease. The Annals of Pharmacotherapy . 2009;43(10):1598–1605. https://doi.org/10.1345/aph.1M187 Doogue MP, Polasek TM. Drug Dosing in Renal Disease. The Clinical Biochemist Reviews . 2011;32(2):69–73. British National Formulary (BNF). Prescribing in renal impairment. National Institute for Health and Care Excellence. 2023. https://bnf.nice.org.uk/medicines-guidance/prescribing-in-renal-impairment/. Accessed 1 May 2023. Parlament Österreich. MTD-Gesetz 2024 – MTDG, Rezeptpflichtgesetz u.a. (996/BNR). Parlament Österreich. 2024. https://www.parlament.gv.at/dokument/XXVII/BNR/996/fname_1642344.pdf. Accessed 3 Aug 2024. Mahase E. Covid-19: NICE plans to expand Paxlovid eligibility to 1.4 million more people. BMJ. 2024;384:59. https://doi.org/10.1136/bmj.q59 Tables Table 1 : Characteristics of patients included in the study (n=140) Characteristics Gender N (%) male 58 (41) female 82 (59) Age, mean ± SD 75.2 ± 14.1 Renal function (eGFR), mean ± SD 71.6 ± 22.1 Renal function n (%) Normal renal function 1 or mild impairment 2 98 (70.0) Moderate impairment 3 39 (27.9) Severe impairment 4 3 (2.1) Concomitant Drugs and Interactions Concomitantly used drugs per patient (n), mean ± SD 9.8 ± 5.0 Interactions identified per patient (n), mean ± SD 2.2 ± 1.8 eGFR… estimated glomerular filtration rate 1 eGFR ≥ 90 ml/min 2 eGFR ≥ 60 to < 90 ml/min 3 eGFR ≥ 30 to < 60 mL/min 4 eGFR < 30 ml/min Table 2 Number of detected interactions per drug of the 20 most frequently found interacting drugs (N= in 239 out of the 313 DDIs identified; multiple interactions per patient were possible due to polypharmacy) Drug Number of interactions (%) Severe (red) interactions 19 (6.1) Quetiapine 9 (2.9) Triazolam 6 (1.9) Simvastatin 4 (1.3) Possible (orange) interactions 177 (56.6) Metamizole 50 (16.0) Amlodipine 29 (9.3) Atorvastatin 27 (8.6) Trazodone 12 (3.8) Rosuvastatin 10 (3.2) Valsartan 9 (2.9) Tamsulosin 9 (2.9) Edoxaban 8 (2.6) Dihydrocodeine 6 (1.9) Doxazosin 6 (1.9) Apixaban 6 (1.9) Alprazolam 5 (1.6) Possible weak (yellow) interactions 43 (13.7) Hydromorphone 20 (6.4) Diosmin 7 (2.2) Mirtazapine 6 (1.9) Ezetimibe 5 (1.6) Macrogol 5 (1.6) Supplementary Files Appendices.docx Cite Share Download PDF Status: Published Journal Publication published 21 Dec, 2024 Read the published version in International Journal of Clinical Pharmacy → Version 1 posted Editorial decision: Major revisions 22 Sep, 2024 Reviewers agreed at journal 27 Aug, 2024 Reviewers invited by journal 26 Aug, 2024 Editor assigned by journal 26 Aug, 2024 First submitted to journal 25 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4973191","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":345187766,"identity":"51bdef74-ff4f-47fc-92a9-ed854e68daf3","order_by":0,"name":"Alina Stoiber","email":"","orcid":"","institution":"Robert Gordon University Garthdee Campus: Robert Gordon University","correspondingAuthor":false,"prefix":"","firstName":"Alina","middleName":"","lastName":"Stoiber","suffix":""},{"id":345187767,"identity":"6842aad4-057a-4e1f-8692-2ec77e095236","order_by":1,"name":"Gwen Gray","email":"","orcid":"","institution":"Robert Gordon University Garthdee Campus: Robert Gordon University","correspondingAuthor":false,"prefix":"","firstName":"Gwen","middleName":"","lastName":"Gray","suffix":""},{"id":345187768,"identity":"0cc92885-564e-426c-8adc-6d2042982a8f","order_by":2,"name":"Gudrun Sailer","email":"","orcid":"","institution":"Vienna Healthcare Group - Campus Ottakring Hospital: Schule fur Gesundheits -und Krankenpflege","correspondingAuthor":false,"prefix":"","firstName":"Gudrun","middleName":"","lastName":"Sailer","suffix":""},{"id":345187769,"identity":"2060cf9f-f8da-41cd-a50b-2be1f82b0b1e","order_by":3,"name":"Wolfgang Huf","email":"","orcid":"","institution":"Institute for clinical risk management","correspondingAuthor":false,"prefix":"","firstName":"Wolfgang","middleName":"","lastName":"Huf","suffix":""},{"id":345187770,"identity":"bf0ff3d1-555f-458c-85f5-421d9835862d","order_by":4,"name":"Antonella Tonna","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwUlEQVRIiWNgGAWjYBADOThLgrBiZjBpTLqWxAaitfA38B98XLjDLn17/xoDhh81DIkzGwhokTjAzGw880xy7pwbbwwYe44xJM4m6K4DzGzSvG3MuTMkzhgw8DYwJM4jpEMeoqU+XQKohfEvMVoMIFoOJ0jw9xgwg2wh6DDDw8zGxrxtxw1nSLAVHJY5JmFM0PtyxxsfPuZtq5aX4D+88eGbGhvZGQcIWcMMY0gkMBwgKiIRgJ+g6aNgFIyCUTBSAQD44DZoZTXHWQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-2659-6901","institution":"Robert Gordon University","correspondingAuthor":true,"prefix":"","firstName":"Antonella","middleName":"","lastName":"Tonna","suffix":""}],"badges":[],"createdAt":"2024-08-25 14:36:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4973191/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4973191/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11096-024-01852-5","type":"published","date":"2024-12-21T15:56:56+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66904840,"identity":"e14c0763-e0ff-4c13-beec-efa3c5596857","added_by":"auto","created_at":"2024-10-17 17:44:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58835,"visible":true,"origin":"","legend":"\u003cp\u003ePathway of prescribing and supplying Paxlovid®\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4973191/v1/9051b0e584e6b29fd77d5877.png"},{"id":72201715,"identity":"aacce7fb-8cac-49c0-b269-b015e212eb28","added_by":"auto","created_at":"2024-12-23 16:10:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":521393,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4973191/v1/8a792fdd-4e3a-412e-b7fa-d2cd40ed2871.pdf"},{"id":66903950,"identity":"0056409a-16f6-4ff4-a8a9-6e8d11891d3c","added_by":"auto","created_at":"2024-10-17 17:36:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17923,"visible":true,"origin":"","legend":"","description":"","filename":"Appendices.docx","url":"https://assets-eu.researchsquare.com/files/rs-4973191/v1/7d04b9d6ab086caf217790a4.docx"}],"financialInterests":"","formattedTitle":"A descriptive analysis of drug related problems identified when prescribing the COVID-19 antiviral drug Paxlovid®","fulltext":[{"header":"Impact on Practice ","content":"\u003cul\u003e\n \u003cli\u003ePharmacist screening for drug related problems at the point of dispensing is likely to increase patient safety and mitigate risk associated with high-risk drugs.\u003c/li\u003e\n \u003cli\u003eThe study confirms that a strong focus needs to be placed on reviewing the patients\u0026acute; renal function and adjusting dosing accordingly both as part of the prescribing and screening processes.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eThe development of vaccines was a significant milestone in the fight against the coronavirus (COVID-19). However, immunosuppressed patients do not respond adequately to the vaccine and require additional protection [1].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVarious treatments preventing the progression of COVID-19 [2] require intravenous administration making accessibility challenging. Paxlovid\u0026reg;, a combination of nirmatrelvir and ritonavir, is the only preparation available orally to treat COVID-19 that is licensed in Europe enhancing accessibility for outpatients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUse of Paxlovid\u0026reg; maybe challenging due to ritonavir\u0026apos;s potent inhibition of Cytochrome P450 enzymes, leading to numerous drug interactions [3-6]. Additionally, nirmatrelvir, when administered in combination with ritonavir, is renally excreted unchanged requiring dose adjustments in patients with moderate renal impairment (eGFR \u0026le; 60 ml/min) [3]. \u0026nbsp;In patients with severe renal impairment (eGFR \u0026lt; 30 ml/min), Paxlovid\u0026reg; is contraindicated [3,7]. Therefore, a comprehensive medication review is imperative for every patient prescribed Paxlovid\u0026reg;. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn view of the above, pharmacists in some countries such as the US and Canada have been authorized to prescribe and dispense Paxlovid\u0026reg; to enhance patient safety [8,9]. In Austria, only doctors can prescribe Paxlovid\u0026reg; [10]. \u0026nbsp; Nevertheless, pharmacists can play an important role in ensuring patient safety by conducting medication reviews and providing support during the prescribing process. A pharmaceutical service involving medication reviews of all patients on Paxlovid\u0026reg; was introduced in an Austrian public hospital (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1 placed here\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe aim was to describe the frequency, type, and severity of detected DRPs with Paxlovid\u0026reg;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committees of Robert Gordon University (1st Feb 2023/S331) and the City of Vienna (10th Mar 2023/EK23-028-VK).\u0026nbsp;\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eA retrospective, single centre, descriptive data analysis was performed in a 750-bed-capacity public hospital in Vienna, Austria. Inpatients who tested positive for COVID-19 and prescribed Paxlovid\u0026reg; were included and identified through the hospital software system. Demographic details of patients prescribed Paxlovid\u0026reg; between September 2022 to March 2023 were collected and recorded in a customized and anonymized Data Collection Tool (DCT) [See Appendix I]. The DCT developed was piloted using 10 patient records where the data was collected by two clinical pharmacists (AS, RC) and independently checked for consistency by a third (GS). Cohen\u0026acute;s kappa statistic was used to check for inter-rater reliability [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] which was 100% for every component. Other information collected included any DDIs identified together with the degree of severity of the interaction as per University of Liverpool interaction checker [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Descriptive statistics were generated and supported by Excel.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003eParticipant characteristics\u003c/h2\u003e\n\u003cp\u003e140 patients were prescribed Paxlovid\u0026reg; during the data collection period with 58 males and a median age of 75.2 years (range 24 - 101 years). All had a medication review performed by a trained clinical pharmacist. \u0026nbsp;The median number of concomitantly used drugs per patient was 9.8 (ranging 1 - 23) with an average of 2.2 (\u0026plusmn; 1.8) interactions with Paxlovid\u0026reg; per patient. Table 1 summarises the characteristics of patients included.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1 placed here\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalysis of all patients prescribed Paxlovid\u0026reg; during the study period indicated that in 12.9% (18 of 140 patients) of patients, no drug related problem (DRP) was identified and therefore no intervention was required. In the other 87.1% (122 of 140) of cases DRPs were identified. In 33 cases these actions were performed by the prescribers at prescribing stage. In 89 (63.6%) cases the required action was not identified at the point of prescribing but during the pharmaceutical medication analysis after Paxlovid\u0026reg; was ordered in the pharmacy. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe nature of the DRPs identified were as follows: in 5.7% (n=8) of patients, a dose reduction of Paxlovid\u0026reg; was recommended or Paxlovid\u0026reg; contraindicated due to the patient\u0026acute;s renal function; in 57.1% (n=80) drug-drug interactions (DDIs) were identified. In 24.3% (n=34) of all cases renal impairment and DDIs were noted.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eDrug-drug interactions and required interventions\u003c/h2\u003e\n\u003cp\u003eMultiple interactions were identified in individuals due to polypharmacy resulting in a total of 313 DDIs identified in 114 patients (81.4%). Sixty-eight drugs were accountable for these DDIs (see Table 2), with nine drugs having the potential to cause severe interactions with Paxlovid\u0026reg; (red). \u0026nbsp;In three cases where Paxlovid\u0026reg; was contraindicated due to severe renal impairment no extended medication review was conducted. In 24 out of 114 patients where interactions were identified at least one was severe (red) interaction, in 86 patients, at least one possible (orange) interaction was identified, while in 4 patients at least one mild (yellow) interaction was identified.\u003c/p\u003e\n\u003cp\u003eFor each of the 313 identified interactions an intervention was recommended based on guidance available in the Liverpool interaction checker. These included the prescribing of a different COVID-19 medication (n = 5; 1.6%), the temporary withdrawal of the patient\u0026rsquo;s regular medication [118 interactions (37.7 %)] during Paxlovid\u0026reg; administration, dose adjustment to the regular medication [33 interactions (10.5 %)] and closer patient monitoring including blood pressure, ECG or drug monitoring [109 interactions (34.8 %)]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 placed here\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ch2\u003ePaxlovid\u0026reg; in patients with decreased renal function\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003e39 out of the 140 screened patients (27.9%) had moderate renal impairment (30 \u0026le; eGFR \u0026lt; 60 ml/min) requiring a dose reduction of Paxlovid\u0026reg;. This had been considered in 14 cases by the prescribing physician but was highlighted and recommended by the designated clinical pharmacists in the other 25 cases. Three out of 140 (2.1%) had severe renal impairment (eGFR \u0026lt; 30 ml/min) with Paxlovid\u0026reg; prescribed despite the contraindication with an alternative recommended by the pharmacist during the screening process.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatement of key findings\u003c/h2\u003e \u003cp\u003eThis study shows that interventions were still required in most of the prescriptions for Paxlovid\u0026reg; screened by the pharmacists, even though screening had routinely been conducted at the point of prescribing. These findings confirm those in the literature which also suggest that collaboration of medical doctors and pharmacists and involvement of clinical pharmacists in screening can lead to reduced rates of DRPs in hospital as well as in community settings [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and weaknesses\u003c/h2\u003e \u003cp\u003eThe strength of the study lies in the way data was obtained with data concerning DDIs collected and rated separately for each drug. The fact that pharmacists in Austria are independent from prescribing decisions ensures objectivity during the screening process. Limitations of this study include the study\u0026rsquo;s small sample size and the monocentric setting limiting the generalizability of the results and the lack of comparable published data since the drug is relatively new.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eInterpretation\u003c/h2\u003e \u003cp\u003eThe results of our study are highly relevant in the context of a US retrospective, observational cohort study that concluded that approximately one third of patients treated with ritonavir-containing COVID therapy may be at risk of major or contraindicated drug-drug interactions requiring a skilled assessment of possible DDIs before prescribing and dispensing the drug [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This is particularly relevant in elderly, patients with comorbidities and women [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA retrospective review of a pharmacist-led dispensing service conducted in a US community pharmacy setting highlighted the ability of pharmacists to identify and address DRPs involving oral COVID-19 drugs [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] with one or more significant DRPs identified in 78% of Paxlovid\u0026reg; prescriptions at the point of dispensing [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Most interventions identified involved DDIs with HMG-CoA reductase inhibitors, calcium channel blockers, fluticasone nasal sprays, benzodiazepines, antiplatelet therapies and alpha-blockers [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. A study reporting a pharmacy service in an ambulatory care setting identified HMG-CoA reductase inhibitors, Tamsulosin, Trazodone, Amlodipine and Apixaban among the top 10 most frequent drugs to interact with Paxlovid\u0026reg; [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Apart from fluticasone nasal spray, the drugs identified are like those in our study.\u003c/p\u003e \u003cp\u003eThe average number of identified possible DDIs with Paxlovid \u0026reg; per patient was slightly higher in our study (2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8) compared to that published by Portman and Scolese (1.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The reason for the deviation is potentially since all possible DDIs were considered in our study while Portman and Scolese only included \u0026acute;significant drug interactions\u0026acute; [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Nevertheless, a similar number of patients were found to have at least one significant interaction with Paxlovid\u0026reg; (80% of patients compared to 81.4% in our study) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEvidence indicates that physicians do not always sufficiently take the patient\u0026acute;s renal function into account when prescribing [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. For example, a study by Hassan et al showed that the involvement of a pharmacist on ward rounds led to increased consideration of relevant dose adjustments due to impaired renal function [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Similarly, in a retrospective review by Kieck et al, dose reduction of Paxlovid\u0026reg; in patients with decreased renal function was not considered by the prescriber but only subsequently implemented by the pharmacists [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Likewise, in our study, patients\u0026rsquo; doses of Paxlovid\u0026reg; were not reduced in response to the patient\u0026rsquo;s renal function, but adjusted only following recommendations by the pharmacists and after the prescription had been issued and during the screening process.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, it is recommended that pharmacists are routinely involved in the process of prescribing highly interactive drugs such as Paxlovid\u0026reg;. Considering the final draft guidance from the National Institute for Health and Care Excellence (NICE) suggesting an extension of the list of categories of patients who test positive for COVID-19 and who should be considered for Paxlovid\u0026reg;, there is a likelihood of an increased use of the drug [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Results are even more significant in view of draft legislation presented by the Austrian Parliament suggesting the legalisation of certain changes in a patient`s medication by hospital pharmacists following medical instruction [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003ch2\u003eConflict of Interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCenter for Disease Control and Prevention (CDC). \u003cem\u003ePeople with Certain Medical Conditions\u003c/em\u003e. CDC. 2023. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Accessed 5 Feb 2023.\u003c/li\u003e\n \u003cli\u003eCenter for Disease Control and Prevention (CDC). \u003cem\u003eCOVID-19 Treatments and Medications.\u003c/em\u003e CDC. 2024. https://www.cdc.gov/coronavirus/2019-ncov/your-health/treatments-for-severe-illness.html. Accessed 12 Feb 2024.\u003c/li\u003e\n \u003cli\u003eElectronic Medicines Compendium (EMC). \u003cem\u003ePaxlovid 150 mg/100 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (emc).\u003c/em\u003e EMC. 2022. https://www.medicines.org.uk/emc/product/13145/smpc. Accessed 5 Feb 2023.\u003c/li\u003e\n \u003cli\u003eLiverpool Interaction Group. \u003cem\u003eEvaluating the drug-drug interaction risk of COVID-19 therapies (licensed or under clinical investigation).\u0026nbsp;\u003c/em\u003eUniversity of Liverpool. 2022. www.covid19-druginteractions.org/prescribing_resources/methods-metabolism. Accessed 5 Feb 2023.\u003c/li\u003e\n \u003cli\u003eHull MW, Montaner JSG. Ritonavir-boosted protease inhibitors in HIV therapy. \u003cem\u003eAnnals of Medicine\u003c/em\u003e. 2011;43(5):375\u0026ndash;388. https://doi.org/10.3109/07853890.2011.572905\u003c/li\u003e\n \u003cli\u003eWorld Health Organization (WHO). \u003cem\u003eWHO model list of essential medicines - 22nd list, 2021\u003c/em\u003e. WHO. 2021. https://www.who.int/publications-detail-redirect/WHO-MHP-HPS-EML-2021.02. Accessed 5 Feb 2023.\u003c/li\u003e\n \u003cli\u003eNational Health Service (NHS). \u003cem\u003eChronic kidney disease - Diagnosis - NHS\u003c/em\u003e. NHS. 2019. https://www.nhs.uk/conditions/kidney-disease/diagnosis/. Accessed 14 Mar 2023.\u003c/li\u003e\n \u003cli\u003eTanne JH. Covid-19: FDA authorises pharmacists to prescribe Paxlovid. \u003cem\u003eBMJ\u003c/em\u003e. 2022;378. https://doi.org/10.1136/bmj.o1695\u003c/li\u003e\n \u003cli\u003eTraynor K. \u003cem\u003eQu\u0026eacute;bec authorizes pharmacists to prescribe Paxlovid\u003c/em\u003e. American Journal of Health-System Pharmacy.\u003cem\u003e\u0026nbsp;\u003c/em\u003e2022;79(14):1126\u0026ndash;1127. https://doi.org/10.1093/ajhp/zxac163\u003c/li\u003e\n \u003cli\u003eBundesministerium f\u0026uuml;r Finanzen. \u003cem\u003eRIS - Rezeptpflichtgesetz - Bundesrecht konsolidiert, Fassung vom 22.03.2023\u003c/em\u003e. Bundesministerium f\u0026uuml;r Finanzen. 2023.https://www.ris.bka.gv.at/GeltendeFassung.wxe?Abfrage=Bundesnormen\u0026amp;Gesetzesnummer=10010351. Accessed 22 Mar 2023.\u003c/li\u003e\n \u003cli\u003eMcHugh M. \u003cem\u003eInterrater reliability: the kappa statistic\u003c/em\u003e. Biochemia Medica, 2012;22(3):276\u0026ndash;282.\u003c/li\u003e\n \u003cli\u003eThe University of Liverpool. \u003cem\u003eLiverpool COVID-19 Interactions\u003c/em\u003e. The University of Liverpool. 2023. https://www.covid19-druginteractions.org/checker#. Accessed 14 Feb 2023.\u003c/li\u003e\n \u003cli\u003eLiverpool Interaction Group. \u003cem\u003eInteractions with Outpatient Medicines \u0026amp; Nirmatrelvir/ritonavir (NMV/r).\u0026nbsp;\u003c/em\u003eUniversity of Liverpool. 2023. www.covid19-druginteractions.org/prescribing_resources/paxlovid-outpatient-medicines. Accessed 15 Feb 2024.\u003c/li\u003e\n \u003cli\u003eKucukarslan SN, Peters M, Mlynarek M et al. Pharmacists on rounding teams reduce preventable adverse drug events in hospital general medicine units. \u003cem\u003eArch Intern Med\u003c/em\u003e. 2003;163(17):2014-2018. https://doi.org/10.1001/archinte.163.17.2014\u003c/li\u003e\n \u003cli\u003eRoblek T, Deticek A, Leskovar B et al. Clinical-pharmacist intervention reduces clinically relevant drug\u0026ndash;drug interactions in patients with heart failure: A randomized, double-blind, controlled trial. \u003cem\u003eInternational Journal of Cardiology\u003c/em\u003e. 2016;203:647-652. https://doi.org/10.1016/j.ijcard.2015.10.206\u003c/li\u003e\n \u003cli\u003eTasaka Y, Tanaka A, Yasunaga A et al. Potential drug-related problems detected by routine pharmaceutical interventions: safety and economic contributions made by hospital pharmacists in Japan. \u003cem\u003eJournal of Pharmaceutical Health Care and Sciences 4\u003c/em\u003e. 2018;33. https://doi.org/10.1186/s40780-018-0125-z\u003c/li\u003e\n \u003cli\u003eIgho-Osagie E, Puenpatom A, Williams MG et al. Prevalence of potential drug-drug interactions with ritonavir-containing COVID-19 therapy. \u003cem\u003eJ Manag Care Spec Pharm\u003c/em\u003e. 2023;29(5):509-518. https://doi.org/10.18553/jmcp.2023.22366\u003c/li\u003e\n \u003cli\u003eKieck D, Mahalick L and Vo TT. Medication-Related Problems Identified and Addressed by Pharmacists Dispensing COVID-19 Antivirals at a Community Pharmacy. \u003cem\u003ePharmacy\u003c/em\u003e. 2023; 11(3):87. https://doi.org/10.3390/pharmacy11030087\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Portman D.B. and Scolese C.J. Facilitating oral COVID-19 therapy utilization through a pharmacy consult service. \u003cem\u003eJAPhA\u003c/em\u003e. 2023; 63(4):1237-1241. https://doi.org/10.1016/j.japh.2023.04.010\u003c/li\u003e\n \u003cli\u003eHassan Y, Al-Ramahi RJ, Aziz NA et al. Impact of a renal drug dosing service on dose adjustment in hospitalized patients with chronic kidney disease. \u003cem\u003eThe Annals of Pharmacotherapy\u003c/em\u003e. 2009;43(10):1598\u0026ndash;1605. https://doi.org/10.1345/aph.1M187\u003c/li\u003e\n \u003cli\u003eDoogue MP, Polasek TM. Drug Dosing in Renal Disease. \u003cem\u003eThe Clinical Biochemist Reviews\u003c/em\u003e. 2011;32(2):69\u0026ndash;73.\u003c/li\u003e\n \u003cli\u003eBritish National Formulary (BNF). Prescribing in renal impairment. National Institute for Health and Care Excellence. 2023. https://bnf.nice.org.uk/medicines-guidance/prescribing-in-renal-impairment/. Accessed 1 May 2023.\u003c/li\u003e\n \u003cli\u003eParlament \u0026Ouml;sterreich. \u003cem\u003eMTD-Gesetz 2024 \u0026ndash; MTDG, Rezeptpflichtgesetz u.a. (996/BNR).\u003c/em\u003e Parlament \u0026Ouml;sterreich. 2024. https://www.parlament.gv.at/dokument/XXVII/BNR/996/fname_1642344.pdf. Accessed 3 Aug 2024.\u003c/li\u003e\n \u003cli\u003eMahase E. Covid-19: NICE plans to expand Paxlovid eligibility to 1.4 million more people. \u003cem\u003eBMJ.\u003c/em\u003e 2024;384:59. https://doi.org/10.1136/bmj.q59\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003cstrong\u003e: Characteristics of patients included in the study (n=140)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.9735%;\"\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;male\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.9735%;\"\u003e\n \u003cp\u003e58 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.9735%;\"\u003e\n \u003cp\u003e82 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003eAge, mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.9735%;\"\u003e\n \u003cp\u003e75.2 \u0026plusmn; 14.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003eRenal function (eGFR), mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.9735%;\"\u003e\n \u003cp\u003e71.6 \u0026plusmn; 22.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003eRenal function n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.9735%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Normal renal function\u003csup\u003e1\u003c/sup\u003e or \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;mild impairment\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.9735%;\"\u003e\n \u003cp\u003e98 (70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Moderate impairment\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.9735%;\"\u003e\n \u003cp\u003e39 (27.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Severe impairment\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.9735%;\"\u003e\n \u003cp\u003e3 (2.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConcomitant Drugs and Interactions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003eConcomitantly used drugs per patient (n), mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.9735%;\"\u003e\n \u003cp\u003e9.8 \u0026plusmn; 5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.0265%;\"\u003e\n \u003cp\u003eInteractions identified per patient (n), mean \u0026plusmn; SD \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.9735%;\"\u003e\n \u003cp\u003e2.2 \u0026plusmn; 1.8\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eeGFR\u0026hellip; \u0026nbsp;estimated glomerular filtration rate\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e eGFR \u0026ge; 90 ml/min\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e2\u003c/sup\u003e eGFR \u0026ge; 60 to \u0026lt; 90 ml/min\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e3\u003c/sup\u003e eGFR \u0026ge; 30 to \u0026lt; 60 mL/min\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e4\u0026nbsp;\u003c/sup\u003eeGFR \u0026lt; 30 ml/min\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u0026nbsp;\u003c/strong\u003eNumber of detected interactions per drug of the 20 most frequently found interacting drugs (N= in 239 out of the 313 DDIs identified; multiple interactions per patient were possible due to polypharmacy)\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"358\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDrug\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of interactions \u0026nbsp;(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSevere (red) interactions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e19 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eQuetiapine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e9 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eTriazolam\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e6 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eSimvastatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e4 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePossible (orange) interactions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e177 (56.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eMetamizole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e50 (16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eAmlodipine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e29 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eAtorvastatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e27 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eTrazodone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e12 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eRosuvastatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e10 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eValsartan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e9 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eTamsulosin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e9 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eEdoxaban\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e8 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eDihydrocodeine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e6 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eDoxazosin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e6 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eApixaban\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e6 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eAlprazolam\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e5 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePossible weak (yellow) interactions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e43 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eHydromorphone\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e20 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eDiosmin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e7 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eMirtazapine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e6 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eEzetimibe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e5 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003eMacrogol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e5 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67.5978%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.4022%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-pharmacy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcp","sideBox":"Learn more about [International Journal of Clinical Pharmacy](https://www.springer.com/journal/11096)","snPcode":"11096","submissionUrl":"https://submission.nature.com/new-submission/11096/3","title":"International Journal of Clinical Pharmacy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4973191/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4973191/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePaxlovid® is the only licensed oral COVID − 19 antiviral containing nirmatrelvir and ritonavir. Ritonavir is a potent inhibitor of cytochrome P450 enzymes resulting in clinically significant drug-drug interactions (DDIs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo describe the frequency, type, and severity of detected drug related problems (DRPs) with Paxlovid®\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study involved a retrospective, quantitative data analysis. All patients prescribed Paxlovid® in a public hospital in Vienna, were included. Data was collected from the patients’ records and recorded on a customised and piloted data collection form. Any DRPs were also noted. The severity of DDIs was classified using an established checker tool.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e122 of 140 (87.1%) patients required interventions to prevent DRPs; 63.6% of cases required intervention by the pharmacist at dispensing. The most common DRPs were DDIs (57.1%). In 24.3% of cases both renal impairment and DDIs were noted. 313 DDIs were recorded in 114 patients; in 24 patients, the interactions recorded were severe. In 3 patients (2.1%), Paxlovid® was prescribed despite being contraindicated due to severe renal impairment requiring pharmacist intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study demonstrated that numerous DRPs involving Paxlovid® were identified by the pharmacist following prescribing. Pharmacists’ involvement in prescribing highly interacting drugs such as Paxlovid® is beneficial to enhance patient safety.\u003c/p\u003e","manuscriptTitle":"A descriptive analysis of drug related problems identified when prescribing the COVID-19 antiviral drug Paxlovid®","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-17 17:36:30","doi":"10.21203/rs.3.rs-4973191/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2024-09-22T15:49:41+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-08-27T17:33:58+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-26T11:36:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-26T05:29:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Pharmacy","date":"2024-08-25T10:34:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-pharmacy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcp","sideBox":"Learn more about [International Journal of Clinical Pharmacy](https://www.springer.com/journal/11096)","snPcode":"11096","submissionUrl":"https://submission.nature.com/new-submission/11096/3","title":"International Journal of Clinical Pharmacy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"63433df1-cc2c-41ed-9fde-2ddd663237f4","owner":[],"postedDate":"October 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-23T16:00:26+00:00","versionOfRecord":{"articleIdentity":"rs-4973191","link":"https://doi.org/10.1007/s11096-024-01852-5","journal":{"identity":"international-journal-of-clinical-pharmacy","isVorOnly":false,"title":"International Journal of Clinical Pharmacy"},"publishedOn":"2024-12-21 15:56:56","publishedOnDateReadable":"December 21st, 2024"},"versionCreatedAt":"2024-10-17 17:36:30","video":"","vorDoi":"10.1007/s11096-024-01852-5","vorDoiUrl":"https://doi.org/10.1007/s11096-024-01852-5","workflowStages":[]},"version":"v1","identity":"rs-4973191","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4973191","identity":"rs-4973191","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}