PMID- 35944126
OWN - NLM
STAT- MEDLINE
DCOM- 20230320
LR  - 20230814
IS  - 1536-3694 (Electronic)
IS  - 0163-4356 (Linking)
VI  - 45
IP  - 2
DP  - 2023 Apr 1
TI  - Therapeutic Drug Monitoring and Dosage Adjustments of Immunosuppressive Drugs 
      When Combined With Nirmatrelvir/Ritonavir in Patients With COVID-19.
PG  - 191-199
LID - 10.1097/FTD.0000000000001014 [doi]
AB  - 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. Coadministration of nirmatrelvir/ritonavir with immunosuppressive 
      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. Although 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 of ISDs and dosing recommendations when coadministered with 
      nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or 
      patients should be given a microdose on day 1, whereas 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.
CI  - Copyright (c) 2022 Wolters Kluwer Health, Inc. All rights reserved.
FAU - Lemaitre, Florian
AU  - Lemaitre F
AD  - Department of Pharmacology, Univ Rennes, CHU Rennes, Inserm, EHESP, IRSET-UMR S 
      1085, Rennes, France.
AD  - INSERM, Centre d'Investigation Clinique 1414, Rennes, France.
FAU - Budde, Klemens
AU  - Budde K
AD  - Department of Nephrology, Charite Universitatsmedizin Berlin, Berlin, Germany.
FAU - Van Gelder, Teun
AU  - Van Gelder T
AD  - Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, 
      Leiden, the Netherlands.
FAU - Bergan, Stein
AU  - Bergan S
AD  - Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, 
      University of Oslo, Norway.
FAU - Lawson, Roland
AU  - Lawson R
AD  - University of Limoges, Inserm U1248, Pharmacology & Transplantation, Limoges, 
      France.
FAU - Noceti, Ofelia
AU  - Noceti O
AD  - National Center for Liver Transplantation and Liver Diseases, Army Forces 
      Hospital, Montevideo, Uruguay.
FAU - Venkataramanan, Raman
AU  - Venkataramanan R
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Department of 
      Pathology, Starzl Transplantation Institute, School of Medicine, University of 
      Pittsburgh, Pittsburgh, Pennsylvania.
FAU - Elens, Laure
AU  - Elens L
AD  - Integrated Pharmacometrics, Pharmacogenetic and Pharmacokinetics Research Group 
      (PMGK), Louvain Drug for Research Institute (LDRI), Catholic University of 
      Louvain (UCLouvain), Brussels, Belgium.
FAU - Moes, Dirk Jan A R
AU  - Moes DJAR
AD  - Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, 
      Leiden, the Netherlands.
FAU - Hesselink, Dennis A
AU  - Hesselink DA
AD  - Erasmus MC Transplant Institute, University Medical Center, Rotterdam, the 
      Netherlands.
FAU - Pawinski, Tomasz
AU  - Pawinski T
AD  - Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 
      Warsaw, Poland.
FAU - Johnson-Davis, Kamisha L
AU  - Johnson-Davis KL
AD  - University of Utah Health Sciences Center and ARUP Laboratories, Salt Lake City, 
      Utah.
FAU - De Winter, Brenda C M
AU  - De Winter BCM
AD  - Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, 
      Rotterdam, the Netherlands.
FAU - Pattanaik, Smita
AU  - Pattanaik S
AD  - Department of Pharmacology, Post Graduate Institute of Medical Education and 
      Research, Chandigarh, INDIA.
FAU - Brunet, Merce
AU  - Brunet M
AD  - Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics 
      Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, 
      University of Barcelona, IDIBAPS, CIBERehd, Spain.
FAU - Masuda, Satohiro
AU  - Masuda S
AD  - Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji 
      Dokkyo University, Japan; and.
FAU - Langman, Loralie J
AU  - Langman LJ
AD  - Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 
      Rochester, Minnesota, USA.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Ther Drug Monit
JT  - Therapeutic drug monitoring
JID - 7909660
RN  - 0 (nirmatrelvir and ritonavir drug combination)
RN  - O3J8G9O825 (Ritonavir)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - 0 (Immunosuppressive Agents)
SB  - IM
MH  - Humans
MH  - *Ritonavir/therapeutic use
MH  - Drug Monitoring
MH  - Cytochrome P-450 CYP3A
MH  - *COVID-19
MH  - COVID-19 Drug Treatment
MH  - SARS-CoV-2
MH  - Immunosuppressive Agents/adverse effects
COIS- F. Lemaitre received research grants from Astellas Pharma, Sandoz ,and Chiesi 
      Pharma (Paid to his institution) and fees to attend meetings from Chiesi Pharma 
      and Sandoz; K. Budde received Honoraria, research grants from Abbvie, Akebia, 
      Alexion, Astellas, Bristol-Myers Squibb, Calliditas, CSL-Behring, Chiesi, 
      Fresenius, Hexal, Hookipa, MSD Sharp & Dohme, Neovii, Novartis, Otsuka, Pfizer, 
      Quark, Sanofi, Shire, UCB Pharma, Veloxis, Vifor, and Vitaeris Pharma; T. Van 
      Gelder received lecture fees and study grants from Chiesi and Astellas, in 
      addition to consulting fees from Roche Diagnostics, Thermo Fisher, Vitaeris, CSL 
      Behring, Astellas, and Aurinia Pharma (all paid to his institution); D. A. 
      Hesselink received lecture fees and consulting fees from Astellas Pharma, Chiesi 
      Pharma, Medincell, Novartis Pharma, Sangamo Therapeutics, and Vifor Pharma. He 
      also received grant support from Astellas Pharma, Bristol-Myers Squibb, and 
      Chiesi Pharma (paid to his institution). S. Masuda received lecture fees from 
      Astellas Pharma, Novartis Pharma, and Otsuka Pharmaceutical Factory. He also 
      received consulting fees from Meiji-Seika Pharma. The remaining authors declare 
      no conflict of interest.
EDAT- 2022/08/10 06:00
MHDA- 2023/03/21 06:00
CRDT- 2022/08/09 14:42
PHST- 2022/04/28 00:00 [received]
PHST- 2022/07/20 00:00 [accepted]
PHST- 2022/08/10 06:00 [pubmed]
PHST- 2023/03/21 06:00 [medline]
PHST- 2022/08/09 14:42 [entrez]
AID - 00007691-202304000-00009 [pii]
AID - 10.1097/FTD.0000000000001014 [doi]
PST - ppublish
SO  - Ther Drug Monit. 2023 Apr 1;45(2):191-199. doi: 10.1097/FTD.0000000000001014.