Coronavirus Disease 2019 (COVID-19) and Transplantation: Pharmacotherapeutic Management of Immunosuppression Regimen

Figures & data

Table 1 A Summary of Medications Used for Management of COVID-19 Patients

Drugs	Pharmacologic Category	Mechanism of Action	Dosage Regimen in COVID-19	References
Lopinavir/Ritonavir	Antiretroviral agent	Lopinavir is an HIV-1 protease inhibitor; ritonavir increases the half-life of lopinavir via inhibiting cytochrome P450	400 mg/100 mg twice daily for 7–14 days	^Citation39,Citation40
Chloroquine/Hydroxychloroquine	Antimalarial (aminoquinoline)	Chloroquine inhibits quinine reductase, an essential enzyme for biosynthesis of sialic acid, which is necessary for virus fusion with host cell	Chloroquine: 400 mg daily for 10–14 days Hydroxychloroquine: 500 mg twice daily for 10 days or 200 mg 3 times daily for 10 days	^Citation30,Citation31,Citation121
Umifenovir	Antiviral agent	Hemagglutinin inhibitor, which inhibits virus membrane fusion with host cell	200 mg every 12 hours for 10 days	^Citation65,Citation66
Ribavirin	Antiviral agent	Inhibits protein synthesis via blocking IMPDH during replication of virus	1200–2000 mg daily divided into twice daily for 5 days	^Citation52,Citation54,Citation55
Remdesivir	Antiviral agent	Interferes with RNA polymerase	200 mg IV stat and then 100 mg daily for 9 days	^Citation58,Citation64
Interferon	Interferons	Increases phagocyte activity of macrophages and augments cytotoxicity of lymphocytes for viral cells	5 million units twice daily via atomic nebulization or SQ administration	^Citation70,Citation75,Citation76
Tocilizumab	Antirheumatic/IL-6 receptor antagonist	Antagonist of intracellular IL-6 receptor	400 mg IV infusion stat	^Citation84

Abbreviations: COVID-19, coronavirus disease 2019; HIV, human immunodeficiency virus; IMPDH, inosine monophosphate dehydrogenase; IV, intravenous; IL, interleukin.

Table 2 Drug Interactions, Side Effects, and Pharmacotherapeutic Considerations with COVID-19 Medications in Transplant Patients

Drugs	Side Effects	Drug–Immunosuppressant Interactions (Risk Rating)	Considerations
Lopinavir/Ritonavir	GI upset, including N/V, skin rash, hypercholesterolemia, increased serum TGs, increased liver enzymes, diarrhea, abdominal pain, dysgeusia, URT infection	May increase serum concentration of everolimus (category=X); concurrent use should be avoided May increase serum concentration of cyclosporine and tacrolimus (category=D); dose reduction or prolongation of dosing interval and monitoring serum concentrations should be considered May increase serum concentration of Sirolimus (category=D); consider avoiding concurrent use Recommended dose of tacrolimus is 0.5 mg every 5–7 days and its plasma concentration should be maintained between 6 and 8 ng/mL. If daily administration of tacrolimus is preferred, the dose of 0.03–0.08 mg daily or to 1/20th–1/50th reduction in daily dose is recommended. Cyclosporine has less severe drug interactions with PIs than tacrolimus Cyclosporine dose should be reduced to 1/5th total daily dose to achieve 100–200 ng/mL (eg, 25 mg every 1–2 days);daily plasma concentration measurement is also recommended	No dose adjustment is suggested in the manufacturer’s labeling for renal and hepatic impairment; use with caution Once-daily dosing in hemodialysis patients should be avoided May prolong QT and PR intervals Metabolized by CYP3A4 and potently inhibits this isoenzyme and CYP2D6 to a lesser extent
Chloroquine/Hydroxychloroquine	Retinopathy and maculopathy (occurred in long-term use), cardiomyopathy resulting in heart failure, QT interval prolongation, increased liver enzymes, bone marrow suppression (rare), hemolytic anemia, hypoglycemia, GI upset, occasional headaches, dizziness, loss of appetite	May increase serum concentration of cyclosporine (category=D); monitoring for increased serum concentrations and toxic effects should be conducted	50% of dose should be administered in patients with GFR <10 mL/min, hemodialysis, and peritoneal dialysis The drug removal by hemodialysis is negligible No dose adjustment is necessary during CRRT No dose adjustment is suggested in the manufacturer’s labeling for hepatic impairment; should be used with caution Should be used cautiously in patients with G6PD deficiency due to a potential for hemolytic anemia Risk factors for QT prolongation, including hypomagnesemia, hypokalemia, and cardiomyopathy, should be evaluated before initiation, and eliminated if possible
Umifenovir	No data available	No data available	Metabolized by liver, particularly CYP3A4, so it should be used with caution in patients with liver failure Its protein binding is high; thus, it should be used cautiously in patients receiving other medications with high protein binding, such as warfarin
Ribavirin	Headache, fatigue, loss of appetite, diarrhea, abdominal pain, dyspepsia, neutropenia, anemia, lymphocytopenia, hemolytic anemia, increased serum bilirubin, musculoskeletal pain, influenza-like symptoms, URT infections	May increase serum concentrations of active metabolites of azathioprine (category=D), especially myelotoxic metabolites; it is suggested to consider alternative agents; monitoring for signs and symptoms of myelosuppression should be conducted	Dose adjustment should be considered in renal impairment, but optimal dose is not defined; 400 mg twice daily could be considered for patients with mild renal impairment (limited data); its use is not recommended in patients with GFR <50 mL/min due to increased risk of hemolytic anemia Its use is contraindicated in hepatic decompensation (Child–Pugh class B and C) Hemolytic anemia 1–2 weeks after initiation of the drug is of great importance (particularly in cardiovascular patients) Concurrent use with bone marrow suppressants, eg, antimetabolites, cotrimoxazole, ganciclovir, and valganciclovir, causes thrombocytopenia and pancytopenia
Remdesivir	Rash, diarrhea, hypotension, increased liver enzymes	Can induce CYP enzymes, including CYP1A2, CYP2B6, and CYP3A4, but currently no data are available regarding its drug–drug interactions.	Remdesivir 100 mg and 5 mg/mL vials should be kept under 30°C and at refrigerated temperatures (2–8°C), respectively, until time of use. The 5 mg/mL vials can be diluted with normal saline and stored for maximum 4 hours at room temperature or 24 hours at refrigerated temperature
Interferons	Fatigue, headache, chills, depression, malaise, neutropenia, granulocytopenia, leukopenia, anemia, thrombocytopenia, increased serum AST, ALT, and ALP, dyspnea, cough	No interactions	It is suggested to permanently discontinue the drug for severe (grade 3) hepatic injury or hepatic decompensation (Child–Pugh class B and C [score >6])
Tocilizumab	Hepatotoxicity, increased serum ALT and AST, injection-site and infusion-related reactions, increased risk of URT infections, neutropenia, leukopenia, thrombocytopenia	Concomitant use with rituximab should be avoided (category=X) May decrease serum concentration of tacrolimus (category=C); monitoring for decreased levels should be conducted	No dose adjustment is necessary in patients with CrCl <30 mL/min No dose adjustment is suggested for patients with hepatic impairment in the manufacturer’s labeling (has not been studied) Initiation of therapy in patients with active hepatic disease or hepatic impairment is not recommended

Abbreviations: TGs, triglycerides; GGT, gamma-glutamyl transferase; ALT, alanine transaminase; N/V, nausea and vomiting; URT, upper respiratory tract; PI, protease inhibitor; CYP, cytochrome; GI, gastrointestinal; CRRT, continuous renal replacement therapy; GFR, glomerular filtration rate; G6PD, glucose-6-phosphate dehydrogenase; AST, aspartate transaminase.

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