Potential drug interactions with nirmatrelvir/ritonavir in critically ill patients with COVID-19 – a retrospective observational study

Jarczak et al., RPS Pharmacy and Pharmacology Reports, doi:10.1093/rpsppr/rqae028

Feb 2025

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Retrospective 500 critically ill COVID-19 patients in Germany showing potential drug-drug interactions with paxlovid in 48% of patients, with higher age and number of comorbidities significantly associated with drug-drug interactions. Authors note that the population that most needs effective treatment also has the greatest risk of drug-drug interactions.

Resistance. Variants may be resistant to paxlovid1-4. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID5.

Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid6. Retrospective studies that do not exclude contraindicated patients may significantly overestimate efficacy.

Black box warning. The FDA notes that "severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with paxlovid"7.

AKI. Kamo et al. show significantly increased risk of acute kidney injury.

Important missing comments or errors? Let us know.

1. Zhou et al., Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system, Science Advances, doi:10.1126/sciadv.add7197.science.org, doi.org.

2. Jochmans et al., The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir, mBio, doi:10.1128/mbio.02815-22.asm.org, doi.org.

3. Lopez et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.springer.com, doi.org.

4. Zvornicanin et al., Molecular Mechanisms of Drug Resistance and Compensation in SARS-CoV-2 Main Protease: The Interplay Between E166 and L50, bioRxiv, doi:10.1101/2025.01.24.634813.biorxiv.org, doi.org.

5. Thomas et al., Nirmatrelvir-Resistant Mutations in SARS-CoV-2 Mpro Enhance Host Immune Evasion via Cleavage of NF-κB Essential Modulator, bioRxiv, doi:10.1101/2024.10.18.619137.biorxiv.org, doi.org.

6. Hoertel et al., Prevalence of Contraindications to Nirmatrelvir-Ritonavir Among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease, JAMA Network Open, doi:10.1001/jamanetworkopen.2022.42140.jamanetwork.com, doi.org.

7. FDA, Fact sheet for healthcare providers: emergency use authorization for paxlovid, www.fda.gov/media/155050/download.fda.gov.

8. Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.iiarjournals.org, doi.org.

Jarczak et al., 15 Feb 2025, retrospective, Germany, peer-reviewed, 9 authors, study period March 2020 - June 2022. Contact: mar.fischer@uke.de.

This Paper Paxlovid All

Potential drug interactions with nirmatrelvir/ritonavir in critically ill patients with COVID-19 -a retrospective observational study

Dominik Jarczak, Christina König, Anka C Röhr, Anika Forstreuter, Thomas Theo Brehm, Julian Schulze Zur Wiesch, Kevin Roedl, Stefan Kluge, Marlene Fischer

doi:10.1093/rpsppr/rqae028/8016069

Objectives Nirmatrelvir/ritonavir is recommended for high-risk patients with COVID-19 to reduce disease progression and mortality. Ritonavir significantly increases the bioavailability of nirmatrelvir and is the most potent irreversible cytochrome P 450 3A4 inhibitor in clinical use, resulting in a substantial risk for drug-drug interactions (DDI). We aimed to analyze the incidence of potential DDI (pDDI) in critically ill patients with SARS-CoV-2 infection. Methods This is a retrospective single-center study in a quaternary care center in Northern Germany. We reviewed electronic health records for demographic characteristics, comorbid conditions, and medication history. The pre-existing comedication was screened for pDDI with nirmatrelvir/ritonavir using publicly available databases. Binary logistic regression was used to identify patient characteristics associated with pDDI. 2.

References

Arbel, Sagy, Hoshen, Battat, Lavie et al., Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge, N Engl J Med

Hammond, Leister-Tebbe, Gardner, Abreu, Wisemandle, Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19, N Engl J Med

Hu, Xiong, Zhu, Zhang, Zhang et al., The SARS-CoV-2 main protease (Mpro): Structure, function, and emerging therapies for COVID-19, MedComm

Loos, Beijnen, Schinkel, The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?, Int J Mol Sci

Marzolini, Kuritzkes, Marra, Boyle, Gibbons et al., Prescribing Nirmatrelvir-Ritonavir: How to Recognize and Manage Drug-Drug Interactions, Ann Intern Med

Mikus, Foerster, Terstegen, Vogt, Said et al., Oral drugs against COVID-19, Dtsch Ärzteblatt Int

Najjar-Debbiny, Gronich, Weber, Khoury, Amar et al., Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients, Clin Infect Dis

Ng, Correia, Seagal, Degoey, Schrimpf et al., Antiviral Drug Discovery for the Treatment of COVID-19 Infections, Viruses

Organization, WHO recommends highly successful COVID-19 therapy and calls for wide geographical distribution and transparency from originator

Owen, Allerton, Anderson, Aschenbrenner, Avery et al., An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19, Science

Trauth, Respiratorische Virusinfektionen, Med Klin -Intensiv Notfallmedizin

Tregoning, Flight, Higham, Wang, Pierce, Progress of the COVID-19 vaccine effort: viruses, vaccines and variants versus efficacy, effectiveness and escape, Nat Rev Immunol

Xiao, Mehta, Curran, Garibaldi, Alexander, Consortium NCCC (N3C). Potential drug-drug interactions among U.S. adults treated with nirmatrelvir/ritonavir: A cross-sectional

DOI record: { "DOI": "10.1093/rpsppr/rqae028", "ISSN": [ "2754-5849" ], "URL": "http://dx.doi.org/10.1093/rpsppr/rqae028", "abstract": "Abstract\n \n Objectives\n Nirmatrelvir/ritonavir is recommended for high-risk patients with COVID-19 to reduce disease progression and mortality. Ritonavir significantly increases the bioavailability of nirmatrelvir and is the most potent irreversible cytochrome P 450 3A4 inhibitor in clinical use, resulting in a substantial risk for drug-drug interactions (DDI). We aimed to analyze the incidence of potential DDI (pDDI) in critically ill patients with SARS-CoV-2 infection.\n \n \n Methods\n This is a retrospective single-center study in a quaternary care center in Northern Germany. We reviewed electronic health records for demographic characteristics, comorbid conditions, and medication history. The pre-existing comedication was screened for pDDI with nirmatrelvir/ritonavir using publicly available databases. Binary logistic regression was used to identify patient characteristics associated with pDDI.\n \n \n Key Findings\n Of 500 critically ill patients with SARS-CoV-2 infection, 362 (72.4%) received pre-existing comedication. A total of 241/500 patients (48.2%) had a medication history prone to pDDI. Antidiabetics, lipid-lowering drugs, and anticoagulants were among the most frequently used agents with a pDDI. Higher age (OR 1.043; 1.028-1.058; p&lt;0.01) and the number of comorbidities (OR 1.229; 1.119-1.350; p&lt;0.01) were significantly associated with pDDI.\n \n \n Conclusion\n The very patient population that may benefit most from treatment with nirmatrelvir/ritonavir also has the greatest risk of pDDI. Polypharmacy is frequently present in these patients and a conscientious check of the comedication is mandatory before a treatment with nirmatrelvir/ritonavir can be initiated.\n ", "author": [ { "affiliation": [ { "name": "Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf , Hamburg,", "place": [ "Germany" ] } ], "family": "Jarczak", "given": "Dominik", "sequence": "first" }, { "affiliation": [ { "name": "Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf , Hamburg,", "place": [ "Germany" ] } ], "family": "König", "given": "Christina", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Pharmacy, General Hospital of Heidenheim , 89522 Heidenheim,", "place": [ "Germany" ] } ], "family": "Röhr", "given": "Anka C", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf , Hamburg,", "place": [ "Germany" ] } ], "family": "Forstreuter", "given": "Anika", "sequence": "additional" }, { "affiliation": [ { "name": "Division of Infectious Diseases, I. Department of Medicine, University Medical Center Hamburg-Eppendorf , Hamburg,", "place": [ "Germany" ] }, { "name": "German Center for Infection Research (DZIF) , Partner Site Hamburg-Lübeck-Borstel-Riems,", "place": [ "Germany" ] } ], "family": "Brehm", "given": "Thomas Theo", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-5033-1938", "affiliation": [ { "name": "Division of Infectious Diseases, I. Department of Medicine, University Medical Center Hamburg-Eppendorf , Hamburg,", "place": [ "Germany" ] } ], "authenticated-orcid": false, "family": "Schulze zur Wiesch", "given": "Julian", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf , Hamburg,", "place": [ "Germany" ] } ], "family": "Roedl", "given": "Kevin", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-8391-3988", "affiliation": [ { "name": "Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf , Hamburg,", "place": [ "Germany" ] } ], "authenticated-orcid": false, "family": "Kluge", "given": "Stefan", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-7530-8155", "affiliation": [ { "name": "Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf , Hamburg,", "place": [ "Germany" ] } ], "authenticated-orcid": false, "family": "Fischer", "given": "Marlene", "sequence": "additional" } ], "container-title": "RPS Pharmacy and Pharmacology Reports", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2025, 2, 15 ] ], "date-time": "2025-02-15T13:27:16Z", "timestamp": 1739626036000 }, "deposited": { "date-parts": [ [ 2025, 2, 15 ] ], "date-time": "2025-02-15T13:27:16Z", "timestamp": 1739626036000 }, "indexed": { "date-parts": [ [ 2025, 2, 16 ] ], "date-time": "2025-02-16T05:06:57Z", "timestamp": 1739682417453, "version": "3.37.1" }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2025, 2, 15 ] ] }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by-nc/4.0/", "content-version": "am", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 2, 15 ] ], "date-time": "2025-02-15T00:00:00Z", "timestamp": 1739577600000 } } ], "link": [ { "URL": "https://academic.oup.com/rpsppr/advance-article-pdf/doi/10.1093/rpsppr/rqae028/61902989/rqae028.pdf", "content-type": "application/pdf", "content-version": "am", "intended-application": "syndication" }, { "URL": "https://academic.oup.com/rpsppr/advance-article-pdf/doi/10.1093/rpsppr/rqae028/61902989/rqae028.pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "286", "original-title": [], "prefix": "10.1093", "published": { "date-parts": [ [ 2025, 2, 15 ] ] }, "published-online": { "date-parts": [ [ 2025, 2, 15 ] ] }, "publisher": "Oxford University Press (OUP)", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://academic.oup.com/rpsppr/advance-article/doi/10.1093/rpsppr/rqae028/8016069" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Potential drug interactions with nirmatrelvir/ritonavir in critically ill patients with COVID-19 – a retrospective observational study", "type": "journal-article" }

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