Early Clinical Experience With Nirmatrelvir/Ritonavir for the Treatment of COVID-19 in Solid Organ Transplant Recipients

David M. Salerno; Douglas L. Jennings; Nicholas W. Lange; Danielle (Bley) Kovac; Tara Shertel; Justin K. Chen; Jessica Hedvat; Jenna Scheffert; Robert S. Brown Jr; Marcus R. Pereira

Disclosures

American Journal of Transplantation. 2022;22(8):2083-2088. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

Compared with the general population, solid organ transplant recipients (SOTR) are at significantly higher risk of morbidity and mortality due to COVID-19.[1,2] With decreased rates of response to SARS-CoV-2 vaccination and the need for ongoing immunosuppression, this high-risk population can potentially benefit from early therapies to mitigate hospital admission and mortality. Unfortunately, the spread of the Omicron variant has decreased the number of effective drug therapies, as both bamlanivimab/etesevimab and casirivimab/imdevimab have diminished efficacy against this variant and were eventually removed from treatment guidelines.[3]

Sotrovimab, a monoclonal antibody product with a unique mechanism of action, is believed to retain efficacy against the original Omicron variant.[3] However, supplies of sotrovimab have been insufficient to meet the high demand and coordinating ambulatory intravenous infusions can often be difficult. Similar logistical issues complicate the outpatient use of IV Remdesivir, despite supportive data.[4] Fortunately, two new oral options were granted emergency use authorization (EUA) by the FDA, and both became available in December of 2021.

One of these oral options, nirmatrelvir co-administered with ritonavir, was shown to reduce the risk of hospitalization or death compared with placebo by 89% in 2,246 unvaccinated patients infected with SARS-CoV-2.[5] However, ritonavir is a potent cytochrome P450 (CYP) 3A and P-glycoprotein inhibitor that complicates the use of commonly used immunosuppressive medications. 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. Here, we report on the first 25 SOTR treated with NR for mild COVID-19 and describe 30-day outcomes as well as the drug–drug interactions with common immunosuppressant medications.

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