Drug-drug interaction between remdesivir and immunosuppressant agents in a kidney transplant recipient.

A 60-year-old man was treated with a regimen of controlled-release tacrolimus (2 mg once daily), everolimus (0.5 mg twice daily), methylprednisolone (4 mg once daily), and mizoribine (100 mg twice daily) as an anti-rejection regimen following living-donor kidney transplantation. One year after transplantation, the recipient was admitted to Mie University Hospital (day X; admission date) to treat coronavirus disease 2019 pneumonia. The latest trough concentrations of tacrolimus and everolimus before admission (day X-65) were 4.5 ng/mL and 4.4 ng/mL, respectively. Since tacrolimus concentration was 4.2 ng/mL on day X+3, the dose was adjusted to 1.5 mg once daily to reach the target concentration of 3.0 ng/mL due to the introduction of remdesivir. After starting remdesivir on day X+4, the increased trough concentrations of tacrolimus on day X+6 (6.9 ng/mL) and everolimus on day X+7 (9.2 ng/mL) were observed, which resulted in dose reduction of tacrolimus (0.5 mg once daily) and discontinuation of everolimus. After discontinuation of remdesivir on day X+9, dose titration of controlled-release tacrolimus and restart of everolimus (0.5 mg twice daily) were performed from day X+15. The dose of controlled-release tacrolimus was titrated and fixed to 2 mg once daily at discharge (day X+21). There was no toxicity due to immunosuppressive agents during hospitalization. This case report indicated that remdesivir might interact with cytochrome P450 3A4 substrates, such as tacrolimus and everolimus, and elevate their blood concentrations under high inflammatory conditions.

Case Report of COVID-19 Infection After Kidney Transplant Treated With Casirivimab-Imdevimab and Mycophenolate Mofetil Changed to Everolimus.

BACKGROUND: Casirivimab-imdevimab is a cocktail of 2 monoclonal antibodies designed to prevent infection by SARS-CoV-2, the virus that causes COVID-19. Casirivimab-imdevimab has been approved in Japan for treating mild to moderate COVID-19; however, to our knowledge, there are no reports of its use after kidney transplant from a live donor. Everolimus, an antineoplastic chemotherapy drug, is expected to be effective in inhibiting the spread of SARS-CoV-2 and preventing its replication, which may facilitate treatment. Here, we report a case of COVID-19 infection after kidney transplant that was initially treated with casirivimab-imdevimab and mycophenolate mofetil but was later changed to everolimus. CASE REPORT: A 47-year-old man underwent living donor kidney transplant from his mother in 2017. Immunosuppression therapy was underway through the administration of tacrolimus, mycophenolate mofetil, and methylprednisolone. In early September 2021, he was diagnosed as having COVID-19 and was hospitalized on day 3. On hospitalization, mycophenolate mofetil was discontinued and casirivimab-imdevimab and heparin were started. The patient started an everolimus regimen on day 5. The clinical course was successful without rejection. There was no exacerbation of COVID-19; the patient's serum creatinine levels and renal function had otherwise remained stable. CONCLUSIONS: We could safely treat a patient with casirivimab-imdevimab after kidney transplant. It is suggested that casirivimab-imdevimab can prevent COVID-19 from becoming severe and can be administered without worsening renal function. In addition, everolimus may have inhibited the spread of the virus and prevented it from replicating.

New Insights into Red Blood Cell Microcytosis upon mTOR Inhibitor Administration.

The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 µM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 µM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size.

Liver transplant immunosuppression during the covid-19 pandemic. / Inmunosupresión en el trasplante hepático en la era covid-19.

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.