1. Therapeutic Drug Monitoring and Dosage Adjustments of Immunosuppressive Drugs When Combined With Nirmatrelvir/Ritonavir in Patients With COVID-19
- Author
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Lemaitre, F., Budde, K., Gelder, T. van, Bergan, S., Lawson, R., Noceti, O., Venkataramanan, R., Elens, L., Moes, D.J.A.R., Hesselink, D.A., Pawinski, T., Johnson-Davis, K.L., Winter, B.C.M. de, Pattanaik, S., Brunet, M., Masuda, S., Langman, L.J., Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Leiden University Medical Center (LUMC), University of Oslo (UiO), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), National Center for Liver Transplantation [Montevideo, Uruguay], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Université Catholique de Louvain = Catholic University of Louvain (UCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Medical University of Warsaw - Poland, University of Utah, Post Graduate Institute of Medical Education and Research [Chandigarh, India] (PGIMER), University of Barcelona, Dokkyo Medical University, Mayo Clinic [Rochester], None, Jonchère, Laurent, Universiteit Leiden, and UCL - SSS/LDRI - Louvain Drug Research Institute
- Subjects
Pharmacology ,Transplantation ,mTOR inhibitors ,[SDV]Life Sciences [q-bio] ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,Tacrolimus ,[SDV] Life Sciences [q-bio] ,[SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences ,Calcineurin inhibitors ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Drug-drug interactions ,Pharmacology (medical) - Abstract
International audience; Nirmatrelvir/ritonavir (Paxlovid®) consists of a peptidomimetic inhibitor (Nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (Ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component. Indeed, ritonavir inhibits the metabolism of nirmatrelvir through cytochrome P450 3A (CYP3A) leading to higher plasma concentrations and a longer half-life of nirmatrelvir. Co-administration of nirmatrelvir/ritonavir with immunosuppressant drugs (ISDs) is particularly challenging given the major involvement of CYP3A in the metabolism of most of these drugs and their narrow therapeutic ranges. Exposure of ISDs will be drastically increased through the potent ritonavir-mediated inhibition of CYP3A, resulting in an increased risk of adverse drug reactions. While a decrease in the dosage of ISDs can prevent toxicity, an inappropriate dosage regimen may also result in insufficient exposure and a risk of rejection. Here we provide some general recommendations for therapeutic drug monitoring (TDM) of ISDs and dosing recommendations when co-administered with nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or patients should be given a microdose on day-1, while cyclosporine dosage should be reduced to 20% of the initial dosage during the antiviral treatment. Dosages of mammalian target of rapamycin inhibitors (m-TORis) should also be adjusted while dosages of mycophenolic acid and corticosteroids are expected to be less impacted.
- Published
- 2023
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