key: cord-0939911-kyd929br
authors: Fishbane, Steven; Hirsch, Jamie S.; Nair, Vinay
title: Special Considerations for Paxlovid Treatment Among Transplant Recipients With SARS-CoV-2 Infection
date: 2022-01-12
journal: Am J Kidney Dis
DOI: 10.1053/j.ajkd.2022.01.001
sha: 7890fa7512aa43719449849f31bd7b0d7d555e5f
doc_id: 939911
cord_uid: kyd929br

nan

enrollment (at the time of this writing the study continues with existing subjects) (4). On November 16, 2021 , the company applied to the FDA seeking emergency use authorization. On December 14, 2021 , Pfizer provided additional information, indicating that "in vitro data confirm that nirmatrelvir is a potent inhibitor of the Omicron 3CL protease… indicat[ing] nirmatrelvir's potential to maintain robust antiviral activity against Omicron" (6). On December 22, 2021, Paxlovid received emergency use authorization (EUA) by the FDA (7). Importantly, the EUA includes a contraindication statement for patients on drugs that are "highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or lifethreatening reactions" (8). The list of contraindicated drugs, however, does not include cyclosporine, tacrolimus, or sirolimus, or indeed any mention of calcineurin inhibitors (CNI) or mTOR inhibitors (mTORi) (8). Consequently, it is likely that Paxlovid will be prescribed to many transplant patients.

While Paxlovid brings great promise to the fight against COVID-19, for transplant patients it causes significant risk related to drug interactions. Generally, patients with transplants are at high risk of COVID-19 morbidity and mortality due to immunosuppression, lack of response to vaccination, and co-morbid conditions (9,10). With the current surge of COVID-19 and the omicron variant, patients will approach providers seeking Paxlovid prescriptionswhich may occur even preemptively, prior to diagnosis of COVID-19. Pfizer stated in a press release, " [Paxlovid] can be prescribed at the first sign of infection or, pending clinical success of the rest of the EPIC development program and subject to regulatory authorization, at first awareness of an exposure" (7). Although patients could benefit greatly from Paxlovid, they may be at significant risk for drug interactions and harm, due to the ritonavir component of Paxlovid, a J o u r n a l P r e -p r o o f particularly potent inhibitor of cytochrome P450 system CYP3A enzymes (11) . The interaction between ritonavir and CYP3A dependent drugs can result in increases in area under the curve blood concentrations of these latter drugs between 1.8 and 20-fold (11) . Since both cyclosporine, tacrolimus, and mTORi's (sirolimus and everolimus) are highly dependent on CYP3A metabolism, their plasma levels on exposure to ritonavir will increase significantly and rapidly. This effect has been seen previously in reports involving HIV positive transplant patients on ritonavir as a single agent, or as part of a combination drug. One report found an increase in tacrolimus trough from 8.7 ng/ml to 106 ng/ml after only 3 days of starting darunavir/ritonavir, despite a 12% reduction in dose (12) . A tacrolimus trough of this level, even if transient, can lead to dangerous side effects including kidney injury, seizures, PRES (posterior reversible encephalopathy) and even death. In other studies, a reduction of CNI dosage of up to 99% --with tacrolimus doses as low as 0.5 mg once every 7 dayswere enough to maintain therapeutic trough levels (13) (14) (15) (16) . The same effect has been noted with sirolimus (17.) It is important to note that in the pivotal EPIC-HR Study of Paxlovid, a highly relevant exclusion criterion was, "current or expected use of any medications or substances that are highly dependent on CYP3A4 for clearance or are strong inducers of CYP3A4" (5). 

Although current experience in dose adjustment does not exist, based on existing data with ritonavir we suggest an empirical reduction or withholding of CNI administration after initiation of Paxlovid and basing subsequent CNI dosing on trough drug levels for at least as long as Paxlovid treatment continues. Once Paxlovid treatment concludes, the original dose of CNI may be resumed but monitoring trough levels for one or two days seems prudent given the circulating half-life of ritonavir is 3-5 hours and its CYP3A effect could last somewhat longer.

The timing of when and how to restart the CNI/mTORi should weigh the urgency of restarting against the possibility of residual CYP3A4 inhibition. It is important to note that these recommendations are only suggestions, and dosing strategies should be individualized based on the ability to obtain immunosuppressive level monitoring as well as baseline CNI dose and CYP3A polymorphisms, if known. Finally, above and beyond drug interactions, Paxlovid also requires renal dose adjustment, with dose reduction suggested for an eGFR between 30 to 60 ml/min/1.73m2, and the drug is not recommended in patients with an eGFR < 30ml/min/1.73m2 (8).

Given the high risk of drug-drug interaction, hospital and health systems should undertake monitoring and decision support for the use of Paxlovid (Box). Like many other forms of patient safety monitoring and drug safety, a multimodal approach is most likely to be effective. We recommend widespread educational outreach through grand rounds and other lectures; email notifications and information embedded within other COVID-19 updates; partnership outreach to local pharmacies alerting them to Paxlovid-CNI/mTORi interactions; interruptive alerts or other point of prescribing notifications embedded within the electronic health record; automated inbox or tasking to prescribing providers; and automated reports to identify all health system or practice patients on chronic CNI/mTORi newly prescribed Paxlovid, which would allow proactive patient contact and CNI/mTORi dose adjustments. Additionally, other therapies for COVID-19 prevention or treatment exist, which may be an alternative to Paxlovid and may mitigate the risks of drug interactions for patients already taking CNI or MTORi's. Tixagevimab/cilgavimab (Evusheld) is a monoclonal antibody for pre-exposure prophylaxis for immunocompromised patients, and sotrovimab is a monoclonal antibody for treatment of COVID-19 with efficacy against the omicron variant.

In conclusion, Paxlovid is a highly promising new drug combination for treatment of COVID-19. In this review we have discussed important safety risks for patients with transplants or kidney disease that this drug conveys. Yet, these patients are at higher risk related to COVID-19, and there is a great need for an efficacious new agent like Paxlovid. Clinicians must individualize treatment, determining whether Paxlovid's substantial efficacy outweighs risks in the context of individual patients. When treatment is initiated caution and vigilance should be maintained and the risk management strategies described above employed as appropriate. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form January 7, 2022.

The emergence of SARS-CoV-2 in Europe and North America

European Respiratory Society COVID-19 Task Force. The impact of therapeutics on mortality in hospitalised patients with COVID-19: systematic review and meta-analyses informing the

European Respiratory Society living guideline

COVID-19 in kidney transplant recipients

Interpreting and addressing suboptimal immune responses after COVID-19 vaccination in solid-organ transplant recipients

Clinical pharmacokinetics and interactions with other anti-HIV agents

Drug-drug interaction in a kidney transplant recipient receiving HIV salvage therapy and tacrolimus

Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients

Effect of highly active antiretroviral therapy on tacrolimus pharmacokinetics in hepatitis C virus and HIV co-infected liver transplant recipients in the ANRS HC-08 study

Concomitant human immunodeficiency virus protease inhibitor therapy markedly reduces tacrolimus metabolism and increases blood levels

Antiretroviral and immunosuppressive drug-drug interactions: an update

Effect of coadministered HIV-protease inhibitors on tacrolimus and sirolimus blood concentrations in a kidney transplant recipient

 Reduce or hold calcineurin inhibitor dose following first dose of Paxlovid  Base subsequent dosing on trough levels  If trough below target goal, administer single dose of calcineurin inhibitor  Resume normal calcineurin inhibitor dose once treatment course of Paxlovid concludes Note that these are only recommendations and should be individualized based on the ability to obtain immunosuppressive level monitoring, as well as baseline calcineurin inhibitor dose and CYP3A polymorphisms, if known. Similar strategies can be employed for other drugs, including MTOR inhibitors.

Health Systems: Educational outreach through all applicable channels  Email notifications and information embedded within other COVID-19 updates  Partnership outreach to pharmacies alerting them to Paxlovid-calcineurin inhibitor interactions  Interruptive alerts or other point of prescribing notifications embedded within the electronic health record  Tasking or inbox alerts to prescribing providers  Automated reports to identify all health system or practice patients on chronic calcineurin inhibitor therapy newly prescribed Paxlovid  Because of the multiple medications that could be affected by Paxlovid treatment, inclusion of pharmacists in medication managementNephrologists, Transplant Programs and Related Providers:  Identify patients in practice currently treated with calcineurin inhibitors  Email or other notification to patients  Discuss potential Paxlovid issues during office visits  Outreach to referring primary care physicians to inform on Paxlovid drug interactions