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      Potential Effects of Remdesivir on Tacrolimus Exposure in Transplant Recipients with COVID-19 Infection

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          Abstract

          Introduction

          Remdesivir has proven to have benefits against COVID-19 infection. However, data supporting drug-drug interactions are insufficient. Clinicians have noticed that calcineurin inhibitor (CNI) levels tend to change after starting remdesivir. This retrospective study aimed to evaluate the effect of remdesivir on CNI levels.

          Methods

          This study included adult, solid organ transplant recipients hospitalized for COVID-19 who received remdesivir while on CNI. Patients were excluded if they started on other medications known to interact with CNI. The primary endpoint was the percentage of change in CNI levels after starting remdesivir. Secondary endpoints included the time until CNI levels reached a maximum increase in trough levels, the incidence of acute kidney injury, and the time until CNI levels normalized.

          Results

          Of the 86 patients screened, 61 were included (56 on tacrolimus and 5 on cyclosporine). Most patients received kidney transplants (44.3%), and baseline demographics were similar among the transplanted organs. The median increase in tacrolimus level after starting remdesivir was 84.8%, and only 3 patients had no significant change in CNI levels. The median increase in tacrolimus level was more pronounced in lung and kidney recipients compared to heart recipients (96.5% vs. 93.9% vs. 64.6 %, respectively). The median time to the maximum increase in tacrolimus trough levels was 3 days, and it took 10 days after the remdesivir course for levels to return to baseline.

          Conclusion

          This retrospective analysis demonstrates that CNI levels were significantly elevated after starting remdesivir. However, future studies are warranted to evaluate this interaction further.

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          Most cited references14

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          Remdesivir for the Treatment of Covid-19 — Final Report

          John H. Beigel, Kay Tomashek, Lori Dodd … (2022)
          Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)
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            A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

            Bin Cao, Yeming Wang, Danning Wen … (2020)
            Abstract Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao 2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao 2) to the fraction of inspired oxygen (Fio 2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. Results A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir–ritonavir group, and 100 to the standard-care group. Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir–ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. Conclusions In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.)
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              A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia.

              Federico Alberici, Elisa Delbarba, Chiara Manenti … (2020)
              The outcome of SARS-CoV2 infection in patients who have received a kidney allograft and are being treated with immunosuppression is unclear. We describe 20 kidney transplant recipients (median age 59 years [inter quartile range 51-64 years], median age of transplant 13 years [9-20 years], baseline eGFR 36.5 [23-47.5]) with SARS-CoV2 induced pneumonia. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/day, all but one was commenced on antiviral therapy and hydroxychloroquine with doses adjusted for kidney function. At baseline, all patients presented fever but only one complained of difficulty in breathing. Half of patients showed chest radiographic evidence of bilateral infiltrates while the other half showed unilateral changes or no infiltrates. During a median follow-up of seven days, 87% experienced a radiological progression and among those 73% required escalation of oxygen therapy. Six patients developed acute kidney injury with one requiring hemodialysis. Six of 12 patients were treated with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor. Overall, five kidney transplant recipients died after a median period of 15 days [15-19] from symptom onset. These preliminary findings describe a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in renal transplant recipients with SARS-Cov2 pneumonia. Thus, in this limited cohort of long-term kidney transplant patients, SARS-CoV-2 induced pneumonia is characterized by high risk of progression and significant mortality.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Kidney Int Rep
                Journal ID (iso-abbrev): Kidney Int Rep
                Title: Kidney International Reports
                Publisher: Published by Elsevier Inc. on behalf of the International Society of Nephrology.
                ISSN (Electronic): 2468-0249
                Publication date PMC-release: 30 April 2023
                Publication date (Electronic): 30 April 2023
                Affiliations
                [a ]Brigham and Women’s Hospital, Boston, MA 02115, USA
                [b ]Department of Clinical Pharmacy, College of Pharmacy, Taibah University, Madinah 42353, KSA
                [c ]Harvard Medical School, Boston, MA 02115, USA
                Author notes
                [∗ ]Corresponding author: Author's 75 Francis St, Department of Pharmacy of Brigham and Women’s Hospital, Boston, MA 02115
                Article
                Publisher Item ID: S2468-0249(23)01292-5
                DOI: 10.1016/j.ekir.2023.04.028
                PMC ID: 10148982
                SO-VID: a8f22ddc-a584-4669-8c0e-74b862ceb7c1
                Copyright © © 2023 Published by Elsevier Inc. on behalf of the International Society of Nephrology.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 4 November 2022
                Date revision received : 18 April 2023
                Date accepted : 24 April 2023
                Categories
                Subject: Clinical Research

                Keywords: remdesivir,tacrolimus,cyclosporin,calcineurin inhibitor,transplant,covid-19 infection,interaction
                Data availability:
                Keywords: remdesivir, tacrolimus, cyclosporin, calcineurin inhibitor, transplant, covid-19 infection, interaction

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