key: cord-0888772-hr3pv3pz
authors: Salerno, David M.; Jennings, Douglas L.; Lange, Nicholas W.; Kovac, Danielle (Bley); Shertel, Tara; Chen, Justin K.; Hedvat, Jessica; Scheffert, Jenna; Brown, Robert S.; Pereira, Marcus R.
title: Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID‐19 in solid organ transplant recipients
date: 2022-03-21
journal: Am J Transplant
DOI: 10.1111/ajt.17027
sha: c0471bf5769224e7e0f46ed5dc59dcbad8b622c2
doc_id: 888772
cord_uid: hr3pv3pz

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.

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.

clinical research/practice, drug interaction, immunosuppressant, immunosuppression/immune modulation, infection and infectious agents-viral: SARS-CoV-2/COVID-19, pharmacology, solid organ transplantation AJT SALERNO Et AL. 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 30day outcomes as well as the drug-drug interactions with common immunosuppressant medications.

In this IRB-approved, retrospective study, all adult SOTR receiving a new prescription for nirmatrelvir/ritonavir between December 28, 2021 and January 6, 2022 were included. Key demographics and background histories were obtained from review of the electronic medical record. The outcomes of interest were the incidence of hospital admission or mortality within 30 days of nirmatrelvir/ritonavir completion as well as immunosuppressant drug levels and dose adjustments. The baseline values represent the last known immunosuppressant trough concentration and dose. Patients were excluded if they did not complete 5 days of nirmatrelvir/ritonavir. Patient follow-up was at least 30 days for all patients with day 1 being the start of nirmatrelvir/ritonavir. All patients were instructed to adhere to the following previously published dosing guideline from our clinical group 6 : hold tacrolimus or mTOR inhibitor or reduce cyclosporine dose to 20% of baseline daily dose. Patients were also routinely instructed to call the transplant clinic if they were to experience any signs/symptoms associated with CNI or mTOR inhibitor toxicity.

A follow-up level was suggested on day 3 of nirmatrelvir/ritonavir (if feasible) and strongly recommended within 1 to 2 days of completing nirmatrelvir/ritonavir. Follow-up laboratory work were obtained via a facility capable of servicing patients with COVID-19.

A total of 25 SOTR were included: kidney = 5 (20%), liver = 2 (8%), heart = 9 (36%), and lung = 9 (36%) (see Table 1 ). All patients com- Table S1 ). One heart transplant recipient did experience a rise in Serum creatinine values were numerically similar, with only one patient experiencing a rise in serum creatinine greater than 0.3 mg/dl between NR start and NR completion. There were also an additional two patients with a similar rise within the 30 day follow-up period.

Liver enzymes and total bilirubin were not routinely checked, but no patients experienced a documented rise of AST/ALT or bilirubin greater than 3x the upper limit of normal.

Pooled studies across a variety of variant-dominated COVID-19

waves indicate significant morbidity and mortality among SOTR compared with that of the non-immunocompromised population. [7] [8] [9] These findings underscore the need to identify safe and effective drug therapies for this vulnerable patient population. While nir- for nirmatrelvir/ritonavir is based on the EPIC-HR phase 2/3, randomized, double-blind, placebo-controlled study in which patients that received nirmatrelvir/ritonavir were shown to have a significant reduction COVID-19 related hospitalization or death. 5 Notably, this study included patients with immunosuppressive disease or immunosuppressive treatment but excluded individuals with a history of prior COVID-19 or vaccination. The incidence of hospitalization or death in our study was higher than that reported in the nirmatrelvir/ritonavir EUA. This is in line with higher rates of hospitalization for COVID-19 in SOTR compared with the general population. 9 This highlights the potential contribution of immunosuppression or comorbidities on COVID-19 outcomes in SOTR. 11 Our findings in this case series, although preliminary, highlight the potential feasibility of managing the drug interaction between NR and key transplant medications using a standardized dosing protocol.

While following the guidance of our previously published protocol, However, the results of our analysis demonstrate that the clinically significant interaction between nirmatrelvir/ritonavir and immunosuppressants can be reasonably managed with a standardized dosing protocol. 6 We consider there are two "phases" of this inter- In terms of safety, there were no patient-reported neurological sequelae in the setting of concomitant use of nirmatrelvir/ritonavir and CNIs. One patient did experience acute kidney injury in the setting of an elevated tacrolimus trough concentration of 24.6 ng/ml (on day 10) after resumption of the full pre-dose on day 7. There were several drug-drug interactions between HMG-CoA reductase inhibitors and antiplatelet agents that did require discontinuation.

Consultation with a transplant pharmacist to help manage these drug interactions were helpful.

Based on the results herein, at the start of nirmatrelvir/ritonavir we propose to hold tacrolimus and mTOR inhibitors and for those patients on cyclosporine to reduce the total daily dose by 80%. Future immunosuppressant dose changes should be made according to the follow-up level. 6 The overall trend in our cohort was for the tacrolimus levels to drop in the setting of holding the drug for the entire course of nirmatrelvir/ritonavir ( Figure 1A ). For the majority of stable, ambulatory SOTR who are currently infected with COVID-19, we feel that this slight decrease would be unlikely to result in adverse immuno- 

COVID-19 in solid organ transplant recipients: initial report from the US epicenter

Mortality in solid organ transplant recipients with COVID-19: more than meets the eye

Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2

Early remdesivir to prevent progression to severe Covid-19 in outpatients

An oral SARS-CoV-2 M

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

Outcomes of COVID-19 in solid organ transplant recipients: a propensitymatched analysis of a large research network

The association between severe or death COVID-19 and solid organ transplantation: a systematic review and meta-analysis

Incidence and outcome of SARS-CoV-2 infection on solid organ transplantation recipients: a nationwide population-based study

An interferon-free antiviral regimen for HCV after liver transplantation

A retrospective matched cohort single-center study evaluating outcomes of COVID-19 and the impact of immunomodulation on COVID-19-related cytokine release syndrome in solid organ transplant recipients

Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir

AST statement on oral antiviral therapy for COVID-19 for organ transplant recipients

Determining the time course of CYP3A inhibition by potent reversible and irreversible CYP3A inhibitors using A limited sampling strategy

Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug interacting effect

close re-assessment and dosing by levels approach. The use of "supplemental" doses for tacrolimus (i.e., 0.5 mg once per week) has been proposed in other treatment protocols of a ritonavir-boosted protease inhibitor regimen. 10 Although we are unable to comment about the benefit of a supplemental dose in the setting of 5 days of ritonavir as this was not part of our current protocol.Our analysis has several important limitations. First, we took a convenience sample population with a relatively limited size, although this was due to a shortage of nirmatrelvir/ritonavir during the peak of Omnicron variant wave in New York City. Second, our analysis does not have a comparator group, which precludes us from determining the efficacy of nirmatrelvir/ritonavir in preventing COVID-19-related hospitalization and death. These limitations notwithstanding, our analysis shows that nirmatrelvir/ritonavir was associated with a relatively low number of COVID-19-related hospitalization and death in SOTR. Furthermore, the use of a standardized dosing protocol can assist clinicians in navigating the drug interaction between nirmatrelvir/ritonavir and immunosuppressive therapy. Although our study has described the short-term safety of nirmatrelvir/ritonavir, future studies with a comparator group are needed to establish the efficacy of nirmatrelvir/ritonavir in SOTR.

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

The data that support the findings of this study are available from the corresponding author upon reasonable request.