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Drug-drug interaction with oral antivirals for early treatment of COVID-19 – Authors’ reply

  • Carsten Schade Larsen
    Correspondence
    Corresponding author: Carsten Schade Larsen, Dept. of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus N, Tel +4525601510.
    Affiliations
    Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
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Open AccessPublished:December 01, 2022DOI:https://doi.org/10.1016/j.ijid.2022.11.038

      Highlights

      • Nirmeltravir/ritonavir is indicated for early treatment of COVID-19.
      • Coadministration of nirmeltravir/ritonavir with simvastatin or lovastatin is contraindicated.
      • The pragmatic solution is to withhold statins during treatment with nirmeltravir/ritonavir.
      • Withholding statins will not expose the patients for an increased risk of cardiovascular events.

      Keywords

      I thank Vuorio et al. [
      • Vuorio A
      • Raal F
      Kovanen PT Drug-drug interaction with oral antivirals for early treatment of COVID-19.
      ] for their very relevant concerns and comments on the Danish population-based study estimating the risk of significant drug-drug-interactions (DDIs) with the oral antiviral nirmatrelvir/ritonavir in the elderly Danish population [
      • Vuorio A
      • Raal F
      Kovanen PT Drug-drug interaction with oral antivirals for early treatment of COVID-19.
      ,
      • Larsen CS.
      Assessing the proportion of the Danish population at risk of clinically significant drug-drug interactions with new oral antivirals for early treatment of COVID-19.
      ].
      The study showed that simvastatin or lovastatin was used by 15.45 % of people ≥65 years and 17.70 % of people ≥80 years [
      • Larsen CS.
      Assessing the proportion of the Danish population at risk of clinically significant drug-drug interactions with new oral antivirals for early treatment of COVID-19.
      ]. Coadministration of simvastatin or lovastatin with ritonavir is contraindicated, as ritonavir increases the concentration of these statins 100-fold with risk of severe toxicity, including rhabdomyolysis [

      Liverpool COVID-19 Interactions. COVID-19 Drug Interactions, https://www.covid19-druginteractions.org/checker; 2022 [accessed 20 November 2022].

      ,
      • Marzolini C
      • Kuritzkes DR
      • Marra F
      • Boyle A
      • Gibbons S
      • Flexner C
      • et al.
      Prescribing Nirmatrelvir-Ritonavir: how to recognize and manage drug-drug interactions.
      ]. In cases where coadministration of nirmatrelvir/ritonavir with a drug is contraindicated, there are three options either pause the drug, replace the drug, or consider another antiviral treatment for early COVID-19 [
      • Marzolini C
      • Kuritzkes DR
      • Marra F
      • Boyle A
      • Gibbons S
      • Flexner C
      • et al.
      Recommendations for the management of drug-drug interactions between the COVID-19 antiviral Nirmatrelvir/Ritonavir (Paxlovid) and comedications.
      ]. Obviously, this decision should be based on an individual basis, considering the risks and benefits.
      Concerning the treatment of patients taking simvastatin or lovastatin with nirmatrelvir/ritonavir, most international guidelines and the Danish national guideline recommend withholding these drugs during and at least 2-3 days after treatment [

      Liverpool COVID-19 Interactions. COVID-19 Drug Interactions, https://www.covid19-druginteractions.org/checker; 2022 [accessed 20 November 2022].

      ,
      • National Institute of Health
      COVID-19 Treatment Guidelines.
      ,

      Danish Health Authority. Midlertidig retningslinje for visitation og behandling med Paxlovid (nir-matrelvir/ritonavir), https://www.sst.dk/-/media/Udgivelser/2022/Corona/Paxlovid/Paxlovid_midlertidigretningslinje.ashx?sc_lang=da&hash=1DF396365FE15FDD50A33E2603EBF0C0; 2022 [accessed 20 November 2022].

      ,
      • University of Michigan, Michigan Medicine
      Management of Paxlovid Drug-Drug-Interactions.
      ]. In general, temporarily pausing statins during early treatment of COVID-19 will, in most cases, not cause any clinical harm but will reduce the risk of toxicities due to DDIs [
      • Marzolini C
      • Kuritzkes DR
      • Marra F
      • Boyle A
      • Gibbons S
      • Flexner C
      • et al.
      Prescribing Nirmatrelvir-Ritonavir: how to recognize and manage drug-drug interactions.
      ,
      • Marzolini C
      • Kuritzkes DR
      • Marra F
      • Boyle A
      • Gibbons S
      • Flexner C
      • et al.
      Recommendations for the management of drug-drug interactions between the COVID-19 antiviral Nirmatrelvir/Ritonavir (Paxlovid) and comedications.
      ]. The meta-analysis by Wu et al. [
      • Wu KS
      • Lin PC
      • Chen YS
      • Pan TC
      • Tang PL.
      The use of statins was associated with reduced COVID-19 mortality: a systematic review and meta-analysis.
      ] shows that statins improve the outcome of COVID-19, including patients with severe COVID-19, with the main outcome being the need for intensive care and death. This is not the target population for treatment with nirmatrelvir/ritonavir, which is used for early treatment of COVID-19.
      I do not question that statins used for primary prevention reduce the risk of major vascular events, nor that an option is to replace simvastatin or lovastatin with pravastatin or fluvastatin. However, the pragmatic approach is to pause any statins during treatment. Although being an infectious disease specialist, I doubt that withholding statins for 8 days will expose the patients to a significantly increased risk of major cardiovascular events.

      Declaration of competing interests

      The authors have no competing interests to declare.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethical approval

      Not applicable.

      References

        • Vuorio A
        • Raal F
        Kovanen PT Drug-drug interaction with oral antivirals for early treatment of COVID-19.
        Int J Infect Dis. 2022; https://doi.org/10.1016/j.ijid.2022.11.039
        • Larsen CS.
        Assessing the proportion of the Danish population at risk of clinically significant drug-drug interactions with new oral antivirals for early treatment of COVID-19.
        Int J Infect Dis. 2022; 122: 599-601https://doi.org/10.1016/j.ijid.2022.06.059
      1. Liverpool COVID-19 Interactions. COVID-19 Drug Interactions, https://www.covid19-druginteractions.org/checker; 2022 [accessed 20 November 2022].

        • Marzolini C
        • Kuritzkes DR
        • Marra F
        • Boyle A
        • Gibbons S
        • Flexner C
        • et al.
        Prescribing Nirmatrelvir-Ritonavir: how to recognize and manage drug-drug interactions.
        Ann Intern Med. 2022; 175: 744-746https://doi.org/10.7326/M22-0281
        • Marzolini C
        • Kuritzkes DR
        • Marra F
        • Boyle A
        • Gibbons S
        • Flexner C
        • et al.
        Recommendations for the management of drug-drug interactions between the COVID-19 antiviral Nirmatrelvir/Ritonavir (Paxlovid) and comedications.
        Clin Pharmacol Ther. 2022; 112: 1191-1200https://doi.org/10.1002/cpt.2646
        • National Institute of Health
        COVID-19 Treatment Guidelines.
        2022 ([accessed 20 November 2022])
      2. Danish Health Authority. Midlertidig retningslinje for visitation og behandling med Paxlovid (nir-matrelvir/ritonavir), https://www.sst.dk/-/media/Udgivelser/2022/Corona/Paxlovid/Paxlovid_midlertidigretningslinje.ashx?sc_lang=da&hash=1DF396365FE15FDD50A33E2603EBF0C0; 2022 [accessed 20 November 2022].

        • University of Michigan, Michigan Medicine
        Management of Paxlovid Drug-Drug-Interactions.
        2022 ([accessed 20 November 2022])
        • Wu KS
        • Lin PC
        • Chen YS
        • Pan TC
        • Tang PL.
        The use of statins was associated with reduced COVID-19 mortality: a systematic review and meta-analysis.
        Ann Med. 2021; 53: 874-884https://doi.org/10.1080/07853890.2021.1933165

      Linked Article

      • Drug-drug interaction with oral antivirals for the early treatment of COVID-19
        International Journal of Infectious DiseasesVol. 127
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          We read with interest the Danish population-based study estimating the risk of significant drug-drug interactions (DDIs) with the antiviral component, nirmatrelvir, of the drug combination nirmatrelvir/ritonavir (NMV/r) in the age groups ≥65 years and ≥80 years [1]. The study highlights the potentially detrimental effects of DDIs if this antiviral treatment is used as part of polypharmacy in this elderly population at a high risk for the progression of SARS-CoV-2 infection to severe COVID-19.
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