Nirmatrelvir/ritonavir use: Managing clinically significant drug-drug interactions with transplant immunosuppressants

Lange, Nicholas W; Salerno, David M.; Jennings, Douglas L.; Choe, Julie C; Hedvat, Jessica; Kovac, Danielle; Scheffert, Jenna; Shertel, Tara; Ratner, Lloyd E.; Brown, Robert S.; Pereira, Marcus R.

doi:10.1111/ajt.16955

Cited by 66 publications

(75 citation statements)

References 6 publications

(6 reference statements)

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“…However, there are some safety concerns regarding molnupiravir, as it can cause mutations in host cells [ 55 ]. Furthermore, nirmatrelvir/PF-07321332 is highly dependent on CYP3A for clearance and could interfere with strong inducers of CYP3A4 or with immunosuppressive agents [ 56 ] and should be used in combination with ritonavir, an inhibitor of CYP3A; however, as CYP3A represents the most important cytochrome P450 for drug metabolism in critical tissues such as the gastrointestinal tract and liver, its inhibition could lead to hepatoxicity. Neither molnupiravir nor nirmatrelvir/PF-07321332 are authorized for use as pre-exposure or post-exposure prophylaxis for the prevention of COVID-19; moreover, the projected cost is around $500 (Paxlovid ® ) to $700 (molnupiravir) per person for a 5-day course.…”

Section: Discussionmentioning

confidence: 99%

Molecular Interactions of Tannic Acid with Proteins Associated with SARS-CoV-2 Infectivity

Haddad

Gaudreault

Sasseville

et al. 2022

IJMS

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The overall impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on our society is unprecedented. The identification of small natural ligands that could prevent the entry and/or replication of the coronavirus remains a pertinent approach to fight the coronavirus disease (COVID-19) pandemic. Previously, we showed that the phenolic compounds corilagin and 1,3,6-tri-O-galloyl-β-D-glucose (TGG) inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 target receptor on the cell membrane of the host organism. Building on these promising results, we now assess the effects of these phenolic ligands on two other crucial targets involved in SARS-CoV-2 cell entry and replication, respectively: transmembrane protease serine 2 (TMPRSS2) and 3-chymotrypsin like protease (3CLpro) inhibitors. Since corilagin, TGG, and tannic acid (TA) share many physicochemical and structural properties, we investigate the binding of TA to these targets. In this work, a combination of experimental methods (biochemical inhibition assays, surface plasmon resonance, and quartz crystal microbalance with dissipation monitoring) confirms the potential role of TA in the prevention of SARS-CoV-2 infectivity through the inhibition of extracellular RBD/ACE2 interactions and TMPRSS2 and 3CLpro activity. Moreover, molecular docking prediction followed by dynamic simulation and molecular mechanics Poisson–Boltzmann surface area (MMPBSA) free energy calculation also shows that TA binds to RBD, TMPRSS2, and 3CLpro with higher affinities than TGG and corilagin. Overall, these results suggest that naturally occurring TA is a promising candidate to prevent and inhibit the infectivity of SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

Molecular Interactions of Tannic Acid with Proteins Associated with SARS-CoV-2 Infectivity

Haddad

Gaudreault

Sasseville

et al. 2022

IJMS

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“…Concerning the metabolism of Nirmatrelvir, a general consideration to convey is the paucity of data and clinical or pharmacological studies about antiviral interactions and side effects. It is claimed that the agent’s metabolism can be decreased when combined with certain calcium channel blockers (CCBs) such as verapamil, nilvadipine, and Nicardipine, with lovastatin and amiodarone [ 117 , 118 ].…”

Section: Potential Impact Of Antivirals On the Cardiovascular System ...mentioning

confidence: 99%

Molecular Insights of SARS-CoV-2 Antivirals Administration: A Balance between Safety Profiles and Impact on Cardiovascular Phenotypes

2022

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The COVID-19 pandemic has resulted in a complex clinical challenge, caused by a novel coronavirus, partially similar to previously known coronaviruses but with a different pattern of contagiousness, complications, and mortality. Since its global spread, several therapeutic agents have been developed to address the heterogeneous disease treatment, in terms of severity, hospital or outpatient management, and pre-existing clinical conditions. To better understand the rationale of new or old repurposed medications, the structure and host–virus interaction molecular bases are presented. The recommended agents by EDSA guidelines comprise of corticosteroids, JAK-targeting monoclonal antibodies, IL-6 inhibitors, and antivirals, some of them showing narrow indications due to the lack of large population trials and statistical power. The aim of this review is to present FDA-approved or authorized for emergency use antivirals, namely remdesivir, molnupinavir, and the combination nirmatrelvir-ritonavir and their impact on the cardiovascular system. We reviewed the literature for metanalyses, randomized clinical trials, and case reports and found positive associations between remdesivir and ritonavir administration at therapeutic doses and changes in cardiac conduction, relatable to their previously known pro-arrhythmogenic effects and important ritonavir interactions with cardioactive medications including antiplatelets, anti-arrhythmic agents, and lipid-lowering drugs, possibly interfering with pre-existing therapeutic regimens. Nonetheless, safety profiles of antivirals are largely questioned and addressed by health agencies, in consideration of COVID-19 cardiac and pro-thrombotic complications generally experienced by predisposed subjects. Our advice is to continuously adhere to the strict indications of FDA documents, monitor the possible side effects of antivirals, and increase physicians’ awareness on the co-administration of antivirals and cardiovascular-relevant medications. This review dissects the global and local tendency to structure patient-based treatment plans, for a glance towards practical application of precision medicine.

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“…Following the FDA EUA of nirmatrelvir/ritonavir (NR), we convened a group of multidisciplinary experts at our center to provide recommendations for managing SOTR on calcineurin inhibitors (CNIs) or mammalian target of rapamycin inhibitors (mTOR) who are to begin treatment with nirmatrelvir/ritonavir. 6 To date, limited data exist describing outcomes of nirmatrelvir/ritonavir in SOTR with COVID‐19 with respect to disease progression or the pharmacokinetic interaction with immunosuppressive agents. The objective of this study was to evaluate the impact of nirmatrelvir/ritonavir use in SOTR on key clinical outcomes and to assess the impact of the drug–drug interaction with CNIs and mTOR inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID-19 in solid organ transplant recipients

Salerno

Jennings

Lange

et al. 2022

American Journal of Transplantation

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Nirmatrelvir/ritonavir (NR) use has not yet been described in solid organ transplant recipients (SOTRs) with mild COVID‐19. The objective was to evaluate outcomes among SOTR and describe the drug–drug interaction of NR. This is an IRB‐approved, retrospective study of all adult SOTR on a calcineurin inhibitor (CNI) or mammalian target of rapamycin inhibitor who were prescribed NR between December 28, 2021 and January 6, 2022. A total of 25 adult SOTR were included ( n = 21 tacrolimus, n = 4 cyclosporine, n = 3 everolimus, n = 1 sirolimus). All patients were instructed to follow the following standardized protocol during treatment with 5 days of NR: hold tacrolimus or mTOR inhibitor or reduce cyclosporine dose to 20% of baseline daily dose. Four patients (16%) were hospitalized by day 30; one for infectious diarrhea and three for symptoms related to COVID‐19. No patients died within 30 days of receipt of NR. Median tacrolimus level pre‐ and post‐NR were 7.4 ng/ml (IQR, 6.6–8.6) and 5.2 (IQR, 3.6–8.7), respectively. Four patients experienced a supratherapeutic tacrolimus concentration after restarting tacrolimus post‐NR. Our results show the clinically significant interaction between NR and immunosuppressive agents can be reasonably managed with a standardized dosing protocol. Prescribers should carefully re‐introduce CNI after the NR course is complete.

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Nirmatrelvir/ritonavir use: Managing clinically significant drug-drug interactions with transplant immunosuppressants

Cited by 66 publications

References 6 publications

Molecular Interactions of Tannic Acid with Proteins Associated with SARS-CoV-2 Infectivity

Molecular Interactions of Tannic Acid with Proteins Associated with SARS-CoV-2 Infectivity

Molecular Insights of SARS-CoV-2 Antivirals Administration: A Balance between Safety Profiles and Impact on Cardiovascular Phenotypes

Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID-19 in solid organ transplant recipients

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