COVID-19: A Review of Potential Treatments (Corticosteroids, Remdesivir, Tocilizumab, Bamlanivimab/Etesevimab, and Casirivimab/Imdevimab) and Pharmacological Considerations

Abstract

Objectives: In light of the ongoing global pandemic, this paper reviews data on a number of potential and approved agents for COVID-19 disease management, including corticosteroids, remdesivir, tocilizumab, and monoclonal antibody combinations. Dose considerations, potential drug–drug interactions, and access issues are discussed. Key findings: Remdesivir is the first antiviral agent approved for the treatment of COVID-19, based on results from large clinical trials showing reduction in recovery time, faster clinical improvement, and decrease in time to discharge with remdesivir. Dexamethasone and tocilizumab have demonstrated mortality benefits in large, randomized controlled trials. Consequently, the use of corticosteroids has become the standard of care for hospitalized patients with severe or critical COVID-19, while tocilizumab is recommended for use in combination with a corticosteroid in certain hospitalized patients. Recently, monoclonal antibody combinations bamlanivimab/etesevimab and casirivimab/imdevimab received emergency use authorizations for use in non-hospitalized patients with mild-to-moderate COVID-19 at high risk of disease progression. Summary: As data from large clinical trials emerge, the paradigm of COVID-19 treatments has shifted significantly. The use of corticosteroids, remdesivir, and tocilizumab depend on disease severity. Emerging data on monoclonal antibody combinations are promising, but further data are required. Pharmacists can play a role in ensuring appropriate access, correct administration, and safe use of COVID-19 treatments and are encouraged to stay abreast of new developments.

Introduction

In December 2019, a cluster of pneumonia cases of unknown etiology was reported in Wuhan, China. On January 7, 2020, scientists isolated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel β-coronavirus that causes coronavirus disease 2019 (COVID-19),¹ and on March 11, 2020, COVID-19 was declared a pandemic by the World Health Organization. Two other severe outbreaks have been reported with β-coronaviruses, SARS-CoV in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012.²

SARS-CoV-2 is an enveloped positive-sense single-stranded ribonucleic acid (RNA) virus, and shares 79.6% genetic identity to SARS-CoV.³ For virus entry, both SARS-CoV and SARS-CoV-2 utilize angiotensin-converting-enzyme-2 (ACE2) receptors, which are highly expressed in the lungs,⁴ cardiovascular tissues, kidneys, and the gastrointestinal system.⁵ Common symptoms include fever, cough, myalgia, chills and dyspnea, and to a lesser extent, headache, diarrhea, and anosmia.⁶ Laboratory abnormalities include normal-to-low white blood cell count, lymphopenia, and elevated transaminases,⁷ with significant elevations of neutrophil, D-dimer, blood urea, and creatinine in severe disease.⁸ Chest computed tomography usually shows ground glass opacity and bilateral patchy shadows. The main criteria for diagnosis of COVID-19 is detection of SARS-CoV-2 RNA via real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, but a combination of clinical presentation, laboratory tests, and radiological results is essential in making an effective diagnosis.

As of March 19, 2021, more than 1 year since the declaration of the pandemic, COVID-19 has been confirmed in over 121 million people worldwide, with more than 2.6 million deaths.⁹ Although most cases are mild, a proportion, particularly the elderly and those with chronic comorbidities can progress to severe complications including acute respiratory distress syndrome (ARDS), multi-organ failure, and death.⁷ The National Institutes of Health (NIH)¹⁰ and Infectious Diseases Society of America (IDSA)¹¹ COVID-19 Treatment Guidelines provide the most up-to-date recommendations on management of COVID-19 based on rapidly evolving data. This paper reviews approved and investigational agents for COVID-19 including corticosteroids, remdesivir, tocilizumab and monoclonal antibodies combinations bamlanivimab/etesevimab and casirivimab/imdevimab, with emphasis on clinical outcomes, pharmacology, administration, and potential drug–drug interactions (DDI) of clinical relevance (Table 1).

Table 1.

Dosing, Administration, and Drug Interactions with Medications Used to Manage COVID-19.

	Dose and administration	Monitoring	Pharmacology	Potential interacting agents	Comments
Dexamethasone	6mg IV/PO once daily for up to 10 days Prednisone: 40 mg once daily or in 2 divided doses Methylprednisolone: 32 mg once daily or in 2 divided doses Hydrocortisone: 160 mg in 2-4 divided doses daily	Hyperglycemia, avascular necrosis, psychiatric effects, hypertension, impaired wound healing, secondary infections	Substrate of CYP3A4	Strong CYP3A4 inhibitors and inducers	Monitor for dexamethasone efficacy/toxicity and adjust dose if necessary
			Inducer of CYP3A4 (moderate)	Substrates of CYP3A4 with narrow therapeutic indices	Use with caution and monitor for substrate drug efficacy. Alternatively, consider use of a non-inducing corticosteroid, such as prednisone, methylprednisolone, or hydrocortisone
Remdesivir	Aged 12 and older and at least 40 kg: 200 mg IV loading dose (day 1), then 100 mg IV daily Formulation for IV administration contains SBECD, a renally cleared solubility enhancer. Not recommended in eGFR <30 mL/min	Renal function, liver function Do not initiate or discontinue if ALT ≥5x ULN during treatment	Substrate of CYP3A4, 2C8, 2D6, OATP1B1, P-gp (in vitro); metabolism primarily via hydrolase activity	Strong CYP3A4 inducers	Potential for decreased exposures of remdesivir; low risk of clinically significant interactions due to IV administration and rapid clearance via hydrolase. Nevertheless, use of strong inducers is not recommended. Remdesivir may be administered with dexamethasone.
			Inhibits CYP3A4, OATP1B1/3, BSEP, MRP4, NTCP (in vitro)	Substrates of these enzymes/transporters	Limited potential for clinically significant interactions due to rapid clearance. May consider administering substrate drugs at least 2 hours after remdesivir
			Induces CYP1A2 and potentially CYP3A4 in vitro	Substrates of CYP1A2 and CYP3A4 with narrow therapeutic indices	Potential loss of efficacy of substrate drugs; clinical significance unclear. Monitor efficacy of substrate drugs
			The main metabolite of remdesivir, GS-441524 is renally cleared and concentrations may be increased in impaired renal function. Severe renal toxicity was observed in rat and monkey studies; relevance for humans is unknown	Drugs which reduce renal function	Avoid coadministration if possible or monitor renal function
Tocilizumab	8 mg/kg actual body weight (up to 800 mg) IV as a single dose	Monitor for infusion-related reactions, neutrophils, platelets, lipids, and liver function tests	Hyperinflammation stimuli may downregulate CYP450 activity; inhibition of IL-6 by tocilizumab may restore CYP450 activity and increase metabolism of substrates	CYP substrates (1A2, 2B6, 2C9, 2C19, 2D6 and 3A4) with narrow therapeutic index such as warfarin, cyclosporine, tacrolimus, sirolimus and theophylline	Monitor for efficacy of substrate drugs and adjust doses if necessary
	Avoid if ALT >5 times ULN, ANC <500 cells/μL, platelets <50 000 cells/μL, significant immunosuppression, high risk for GI perforation, or uncontrolled serious infections		Increased risk of immunosuppression	Other monoclonal antibodies, TNF antagonists, IL-1R antagonists, immunosuppressants	Avoid coadministration
Monoclonal antibody cocktails •Bamlanivimab plus etesevimab (BAM/ETE) •Casirivimab plus imdevimab (REGEN-COVTM)	Aged 12 and older and at least 40 kg •Single IV dose of BAM 700 mg and ETE 1400 mg •Single IV dose of casirivimab 1200 mg and imdevimab1200 mg Minimum infusion time depends on bag size Solutions must be diluted prior to administration	Monitor during infusion and for at least 1 hour post-infusion for infusion-related reactions, including anaphylaxis	Not metabolized by CYP450 enzymes, not renally excreted	None anticipated
			Monoclonal antibodies bind the spike proteins of SARS-CoV-2 and block attachment to the human ACE2 receptors	Potential interference with immune responses induced by COVID-19 vaccines	Defer COVID-19 vaccine for at least 90 days after treatment with a SARS-CoV-2 monoclonal antibody cocktail

Abbreviation: ALT, alanine transferase; ANC, absolute neutrophil count; BSEP, bile salt export pump; CYP, cytochrome; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; IL, interleukin; IV, intravenous; OATP, organic anion transporter polypeptide; MRP, multi-drug resistant protein; NTCP, sodium taurocholate cotransporting polypeptide; ULN, upper limit of normal.

Corticosteroids

Patients with severe COVID-19 may develop a hyper-inflammatory response that can lead to severe lung injury, multiorgan dysfunction, and death.¹² Corticosteroids have potent antiinflammatory properties that may mitigate these detrimental effects by preventing an extended cytokine response and promoting the resolution of inflammation. Early in the pandemic, the use of corticosteroids for COVID-19 was widely debated due to reports of lack of clinical benefit and possible harm such as delayed viral clearance, avascular necrosis, and diabetes as observed with use in previous outbreaks of SARS-CoV and MERS-CoV.^13,14 However, data have since emerged to support corticosteroid use for COVID-19 in certain patients.

Recommendations on the use of low-dose corticosteroids for COVID-19 are largely based on the results from the RECOVERY trial, a large, multicenter, randomized open-label study.¹⁵ The trial assessed all-cause mortality at 28 days in hospitalized patients with COVID-19 who received up to 10 days of dexamethasone 6 mg orally (PO) or intravenously (IV) daily added to standard of care (n = 2104) or standard of care alone (n = 4321). Mortality at 28 days was lower among patients who were randomized to receive dexamethasone (22.9% vs 25.7%; RR .83; 95% CI, .75-.93). Survival benefit was greatest among patients receiving invasive mechanical ventilation (29.3% vs 41.4%; RR .64; 95% CI, .51-.81) and persisted among those requiring supplemental oxygen without invasive mechanical ventilation (23.3% vs 26.2%; RR .82; 95% CI, .72-.94), but not among patients who were not requiring respiratory support (17.8% vs 14%; RR 1.19; 95% CI, .91-1.55).

The WHO REACT Working Group conducted a metaanalysis of 7 randomized clinical trials to evaluate the association between corticosteroid and 28-day all-cause mortality in critically ill patients (91% on mechanical ventilation) with COVID-19 (678 received corticosteroids and 1025 received usual care or placebo).¹⁶ Corticosteroid use was associated with lower 28-day mortality rate (32.7% vs 41.5%; OR .66; 95% CI, .53-.82). Decreased all-cause mortality was associated with dexamethasone (OR, .64; 95% CI, .5-.82), but not with hydrocortisone (OR, .69; 95% CI, .43-1.12) nor with methylprednisolone (OR, .91; 95% CI, .29-2.87); the evidence of benefit was strongest with dexamethasone as most of the participants were from the RECOVERY trial. The optimal dose and duration of corticosteroids could not be assessed in this analysis, but there was no evidence to suggest that a higher dose was associated with greater benefit. Various dosages and durations of corticosteroids were studied in several smaller randomized controlled trials, but some of them were halted after publication of the RECOVERY trial results.^17-21

The NIH Guidelines recommend dexamethasone for use in hospitalized patients with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).¹⁰ Similarly, the IDSA Guidelines recommend dexamethasone for hospitalized patients on mechanical ventilation or ECMO, and suggest use in hospitalized patients with SpO₂ ≤94% on room air or requiring supplemental oxygen.¹¹ Both guidelines recommend dexamethasone 6 mg IV or PO once daily for 10 days or until discharge. If dexamethasone is unavailable, equivalent total daily doses of alternative PO or IV glucocorticoids may be used (Table 1).

Patients on corticosteroids should be closely monitored for adverse effects such as hyperglycemia, avascular necrosis, psychiatric effects, hypertension, impaired wound healing, and secondary infections. Dexamethasone and other corticosteroids are CYP3A4 substrates.²² Drugs which inhibit CYP3A4 (e.g., azoles, protease inhibitors, and erythromycin) may increase plasma concentrations of corticosteroids. Monitoring should be done for adrenal insufficiency, Cushing’s syndrome, and other corticosteroid-associated toxicities. Dexamethasone is also a moderate inducer of CYP3A4, and may decrease plasma concentrations and efficacy of other CYP3A4 substrates, such as calcium channel blockers, sedatives, statins, and rilpivirine. If possible, an alternative corticosteroid with non-enzyme inducing properties, such as prednisone, methylprednisolone, or hydrocortisone can be considered. If coadministration with dexamethasone is necessary, the efficacy of concomitant agents should be monitored with dose adjustment if necessary. Enzyme induction effects of dexamethasone may take a few weeks to dissipate after discontinuation. Depending upon the therapeutic index of potentially impacted substrates, higher doses may need to be continued for up to 2 weeks following completion of dexamethasone therapy in order to maintain therapeutic exposures. Close monitoring for drug efficacy and toxicity is recommended.

Remdesivir

Remdesivir (RDV) is currently the only antiviral drug approved by the Food and Drug Administration (FDA) for the treatment of COVID-19.²³ It is indicated for hospitalized adults and pediatrics aged 12 years and older who weigh at least 40 kg. Initially developed for the treatment of Ebola virus infection, RDV is a nucleotide analogue prodrug that is metabolized to the pharmacologically active triphosphate. It inhibits viral replication by binding to the viral RNA-dependent RNA polymerase, resulting in premature chain termination. As of October 2020, RDV is available directly from the distributor (AmerisourceBergen) and costs $3120 for a 5-day treatment course ($520 per vial) for United States (US) hospitals that are not federal entities (Veterans Health Administration, Indian Health Service, the US Coast Guard).²⁴ The FDA approval of RDV in October 2020 was based on a number of published clinical trials.

The Adaptive COVID-19 Treatment Trial (ACTT-1) included hospitalized patients with mild-to-severe COVID-19 and compared treatment with RDV for up to 10 days (n = 541) with placebo (n = 521).²⁵ Most of the patients (90%) had severe disease, and the median time to treatment initiation was 9 days. The study showed faster recovery with RDV (median, 10 vs 15 days; RR 1.29; 95% CI 1.12-1.49). Benefit of RDV for reducing recovery time was greater in patients treated within 10 days of symptom onset; it was also observed in patients who required supplemental oxygen. However, a difference was not observed in patients requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or ECMO and in those not on supplemental oxygen. Limitations of this study include a small sample size and limited power to detect differences in mortality and within subgroups.

In the open-label phase 3 SIMPLE trial, severe COVID-19 patients not requiring mechanical ventilation or ECMO were randomized to 10 days of RDV (n = 197) vs 5 days (n = 200).²⁶ At baseline, more patients in the 10-day group had more severe disease (more mechanical ventilation, ECMO, high-flow oxygen support). Clinical improvement at day 14 was similar between the 2 groups (P = .14). The median duration of hospitalization among patients discharged on or before day 14 was similar between the 5-day (median, 7 days; IQR, 6-10) and 10-day group (median, 8 days; IQR, 5-10).

The phase 3 SIMPLE II trial compared 10 days of RDV (n = 193) and 5 days of RDV (n = 199) with standard of care (n = 200) in hospitalized patients with moderate COVID-19.²⁷ On day 11, patients in the 5-day RDV group had higher odds of improvement in clinical status than those receiving standard of care (OR, 1.65; 95% CI, 1.09-2.48). However, there was no difference in the odds of improvement between the 10-day RDV and standard of care groups (OR, 1.31; 95% CI, .88-1.95). Given no difference in baseline characteristics, the difference in improvement between the 5-day and 10-day RDV arms confer uncertain conclusion.

The interim results from the SOLIDARITY Trial, a large open-label, adaptive randomized controlled trial conducted in 30 countries, with one arm receiving RDV (n = 2743) vs control (n = 2708), showed no difference in in-hospital mortality (11% vs 11.2%; RR .95; 95% CI, .81-1.11).²⁸ Two-thirds of patients in each arm were on supplemental oxygen, and only 9% were on mechanical ventilation. Limitations of this study include variation in the standard of care between countries and the absence of assessing other potentially important outcomes such as clinical improvement, recovery time, and duration of hospitalization.

Recommendations on use of RDV vary according to COVID-19 disease severity. The NIH Guidelines recommend RDV for use in hospitalized patients who require supplemental oxygen.¹⁰ The IDSA Guidelines provide recommendation for a broader patient population and suggest use in hospitalized patients with severe COVID-19, defined as those with SpO₂ ≤94% on room air and patients who require supplemental oxygen, mechanical ventilation, or ECMO.¹¹ However, if RDV supply is limited, the IDSA Guidelines offer consideration for those on supplemental oxygen rather than on mechanical ventilation or ECMO based on observed benefit in patients on supplemental oxygen in the ACTT-1 trial.²⁵ The NIH Guidelines recommend against the use of RDV monotherapy in patients requiring mechanical ventilation or ECMO.¹⁰ For hospitalized patients not requiring supplemental oxygen, RDV use is not recommended by the IDSA Guidelines while the NIH Guidelines offers no recommendations due to insufficient data in this population. The role of RDV in non-hospitalized patients with mild-to-moderate COVID-19 is currently unknown. An ongoing clinical trial is underway to evaluate the efficacy of RDV in reducing hospitalization in an outpatient setting.²⁹

The recommended adult dosage is 200 mg IV on day 1 followed by 100 mg once daily for up to a total of 10 days depending on oxygen requirement and clinical improvement.²³ The main metabolite of RDV, GS-441524, is renally cleared and concentrations may be increased in renal impairment. In animal studies involving rats and monkeys, severe renal toxicity was observed, but the mechanism and relevance for humans is unknown. In addition, RDV formulation contains a renally cleared solubility enhancer, sulfobutylether β-cyclodextrin sodium. Therefore, RDV administration is not recommended in patients with estimated glomerular filtration rate (eGFR) <30 mL/minutes/1.73 m² unless potential benefits outweigh risk. Concomitant use of other nephrotoxic agents should be avoided if possible. In the SIMPLE-Moderate study, 870 patients with confirmed moderate COVID-19 disease and eGFR greater than 50 mL/minutes/1.73 m² received RDV vs 199 patients who received standard of care.³⁰ Baseline demographics and eGFR were similar between groups. Acute kidney injury (AKI) was observed less frequently in participants receiving RDV compared to standard of care (7% vs 10%, P = .03). There was no difference in AKI in participants with a history of chronic kidney disease (CKD) and no significant difference in eGFR over time between study arms.

Infusion-related reactions and elevated transaminases have been observed, and administration should be discontinued if alanine aminotransferase (ALT) increases to >10 times the upper limit of normal (ULN) or if ALT elevation is accompanied by signs or symptoms of liver inflammation.

Although RDV is a substrate for CYP3A4, CYP2C8, CYP2D6, and transporters of OATP1B1 and P-gp in vitro, metabolism is predominantly mediated by hydrolase activity.²³ While caution is advised with concomitant strong CYP3A4 inducers due to possible reduction in RDV exposures, the potential for significant interactions is likely minimized by IV route of administration and rapid clearance by hydrolase activity. Nevertheless, the product insert states that concomitant use of strong inducers such as rifampin is not recommended. Dexamethasone, a moderate CYP3A4 inducer, is unlikely to cause clinically significant reduction in RDV exposure due to rapid clearance and short duration of treatment in COVID-19. RDV is an inhibitor of CYP3A4, OATP1B1/3, BSEP, MRP4, and NTCP in vitro, but the potential for interactions is limited due to its rapid clearance. When co-administering with substrates of these enzymes/transporters with narrow therapeutic indices, consideration may be given to dosing substrate drugs at least 2 hours after RDV to minimize this potential effect.²³ RDV has also been shown to induce CYP1A2 and potentially CYP3A4 in vitro; this is unlikely to be clinical significant, especially given the limited duration of RDV treatment. A synergistic effect on suppression of SARS-CoV-2 replication in vitro has been suggested between cobicistat and RDV, but the clinical relevance of this is unclear.³¹

Tocilizumab

COVID-19 patients may experience a cytokine storm or cytokine release syndrome (CRS), which is an overreaction of the immune system, characterized by the release of IL-6, IL-1, IL-2, IL-8, TNFα, and other inflammatory mediators.³² Excessive cytokine release activates immune cells to release free radicals, resulting in ARDS, multiorgan failures, and potentially death. Elevated markers of hyperinflammation, including IL-6, ferritin, C-reactive protein (CRP), D-dimer, and lactate dehydrogenase, suggesting complications with CRS, have been observed in severe COVID-19.³³ Modulating the levels of proinflammatory IL-6 may decrease the duration and severity of COVID-19. Tocilizumab (TOCI), a humanized monoclonal IL-6 receptor antagonist, is FDA-approved for rheumatoid arthritis and giant cell arteritis.³⁴ Data from 2 large, randomized controlled studies, REMAP-CAP³⁵ and RECOVERY³⁶ trials, have demonstrated a mortality benefit associated with use of TOCI when administered with corticosteroids in select populations of hospitalized patients.

The REMAP-CAP trial evaluated critically ill patients within 24 hours of respiratory or cardiovascular support in an intensive care unit (ICU) who received TOCI (n = 353) or standard of care (n = 402) within 48 hours of randomization.³⁵ Compared to standard of care, use of TOCI reduced in-hospital mortality (28% vs 36%) with median adjusted odds ratios for in-hospital survival of 1.64 (95% CI, 1.18-2.35). The number of organ support-free days was higher in the TOCI group (median, 10 vs 0 day; OR 1.64; 95% CI, 1.25-2.14). The estimated treatment effect in patients treated with TOCI and corticosteroids was greater than that for any intervention on its own. Limitations of this study include the open-label design, missing data due to preliminary report, and limited long-term outcomes.

The RECOVERY trial randomized hospitalized patients with COVID-19 in the United Kingdom (UK) to several possible treatment options.³⁶ A subset of participants with oxygen saturation <92% on air or requiring supplemental oxygen and CRP ≥75 mg/L was randomized to receive TOCI (n = 2022) or standard of care (n = 2094). At baseline, 14% received invasive mechanical ventilation, 41% non-invasive respiratory support, and 45% required no support other than oxygen. Most (82%) of the patients received concomitant corticosteroids. Non–peer-reviewed preliminary data showed that TOCI reduced all-cause mortality through day 28 (29% vs 33%; RR .86; 95% CI, .77-.96). Use of TOCI was associated with a higher possibility of discharge alive from hospital within 28 days (54% vs 47%; RR 1.22; 95% CI, 1.12-1.34). In the subgroup analysis, mortality benefit was only observed in patients who were also receiving corticosteroids (27% vs 33%; RR, .8; 95% CI, .7-.9); no differences were observed with different levels of respiratory support at baseline. Limitations of this study include the open-label design, missing data due to preliminary report, a high percentage of patients randomized to TOCI not receiving treatment (17%), and short-term follow up.

Prior to these 2 large clinical trials, results from early studies produced conflicting findings, which were limited by heterogenous study populations, low statistical power, and low percentage of corticosteroids use.^37-39 However, one study, the EMPACTA trial, also found that TOCI reduced the likelihood of progression to the composite outcome of mechanical ventilation or death.⁴⁰ It is important to note that most of the patients (80%) in this study received concomitant corticosteroids.

The NIH Guidelines recommend a single IV dose of TOCI (8 mg/kg, up to 800 mg) in combination with dexamethasone or equivalent corticosteroid in recently hospitalized patients exhibiting rapid respiratory decompensation due to COVID-19.¹⁰ These patients include those admitted to the ICU within the prior 24 hours who require invasive/non-invasive mechanical ventilation or high-flow oxygen; non-ICU patients with rapid increases in oxygen requirement and sign of significant inflammation (e.g., CRP >75 mg/L). Similarly, the IDSA Guidelines suggest the use of TOCI with corticosteroids in hospitalized patients with progressive severe (requiring supplemental oxygen) or critical (on mechanical ventilation/ECMO) COVID-19 who have significant inflammation (e.g., CRP ≥75 mg/L).¹¹

Administration of TOCI may increase risks of immunosuppression and infections.³⁴ Therefore, it should be avoided in patients with significant immunosuppression, ALT >5 times ULN, absolute neutrophil count <500 cells/μL, platelet count <50 000 cells/μL, those at high risk for gastrointestinal perforation, or other uncontrolled serious infections.¹⁰

Tocilizumab has no inhibitory/inducing effects on CYP450.³⁴ However, CYP450 activity in the liver is down-regulated by infection and hyperinflammation stimuli; thus, IL-6 inhibition with TOCI in chronic inflammatory disease may restore CYP450 activities to higher levels, leading to increased metabolism of drugs that are substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Such interactions may be clinically relevant for CYP450 substrates with narrow therapeutic index.⁴¹ For example, simvastatin exposures were decreased by 57% after TOCI infusion in patients with rheumatoid arthritis.⁴² Because the cytokine storm that occurs with COVID-19 is acute, and treatment with TOCI is initiated rapidly, adjustments may not be necessary. Close monitoring of effects or drug concentrations is recommended for agents with narrow therapeutic index, such as warfarin, cyclosporine, tacrolimus, sirolimus, and theophylline, with dose titration as needed to maintain therapeutic effect. Concomitant administration of TOCI with other monoclonal antibodies, TNF antagonists, IL-1R antagonists, and immunosuppressants should be avoided due to increased risks of immunosuppression and infection.³⁴

Supply of TOCI is generally limited due to cost. The average wholesale price of an 800-mg dose of TOCI is approximately $5000.⁴³

Monoclonal Antibodies

Monoclonal antibodies (mAbs) which target the spike (S) protein of SARS-CoV-2 have the potential to prevent development of infection in people with high-risk exposures, as well as to improve symptomatology and limit progression to severe disease in patients with mild-to-moderate COVID-19. There are a number of mAbs under investigation. Emergency use authorizations (EUA) have been granted for the combinations of bamlamivimab (BAM) plus etesevimab (ETE) and for casirivimab (CAS) plus imdevimab (IMD). The average cost for the administration of BAM/ETE and CAS/IMD is around $310 per dose.⁴⁴ Medicare will pay 95% of the average wholesale price for mAB purchased by health care providers to furnish in the physician office setting.

Bamlanivimab Plus Etesevimab

In February 2021, the FDA issued an EUA for BAM 700 mg/ETE 1400 mg in patients with mild-to-moderate COVID-19 who are at high risk for progressing to severe COVID-19 and/or hospitalization.⁴⁵ This includes patients with a body mass index (BMI) of ≥35 kg/m², CKD, diabetes, immunosuppressive disease, age ≥65, or those with other high-risk comorbidities. BAM and ETE are both recombinant neutralizing human immunoglobulin G-1 variant mAbs that bind the S proteins of SARS-CoV-2 and block attachment to the human ACE2 receptors. They bind to different but overlapping epitopes in the receptor binding domain of the spike protein; combination use is expected to reduce the risk of viral resistance.

In the Phase 3 portion of the BLAZE-1 trial, 1035 ambulatory patients with mild-to-moderate COVID-19 disease were randomized to receive either a single IV dose of BAM 2800 mg/ETE 2800 mg or placebo, within 3 days of diagnosis.⁴⁶ A 70% reduction in COVID-19-related hospitalization or death was observed in the BAM/ETE vs placebo group (95% CI, −7.4 to −2.3, P = .0004). No deaths were reported in the BAM/ETE group vs 10 (at least 8 which were designated related to COVID-19). Participants in the BAM/ETE arm had faster symptom resolution (8 vs 9 days, P = .007). Similar rates of adverse events were observed in both study arms.

Because of the larger sample size and higher number of clinical events in the BLAZE-1 Phase 3 trial, the NIH Guidelines have greater confidence in the evidence for the clinical efficacy of BAM/ETE than that for other mAb options.¹⁰ As such, when available, BAM/ETE should be used for high-risk outpatients according to the EUA. Similarly, the IDSA Guidelines suggest BAM/ETE for use among ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease.¹¹ Treatment should be started as soon as possible after detection of SARS-CoV-2 and within 10 days of symptom onset.⁴⁵ Due to concerns of worsening clinical outcomes associated with mAb when administered to hospitalized patients requiring high flow oxygen or mechanical ventilation, BAM/ETE is not authorized for use in hospitalized patients or in those who require supplemental or increasing oxygen from baseline due to COVID-19. More recent data suggest that BAM/ETE is unlikely to be active against B.1.351 (South Africa) and P.1 (Brazil) variants.

The currently authorized dose in the EUA (BAM/ETE 700/400 mg) is expected to have similar clinical effect to the dose (BAM/ETE 2800/2800 mg) studied in the BLAZE-1 Phase 3 trial based on preliminary data from BLAZE-4 study and pharmacokinetic/pharmacodynamic modelling.⁴⁵ BAM and ETE are administered together as a single IV infusion over at least 60 minutes via pump or gravity. Drug–drug interactions are not expected with BAM/ETE, as they are not renally excreted or metabolized by CYP450 isoenzymes.

Casirivimab Plus Imdevimab

Casirivimab (CAS) plus imdevimab (IMD), or REGEN-COV^TM are 2 recombinant human mAbs which bind to non-overlapping epitopes of the spike protein receptor binding domain of SARS-CoV-2 and block binding to the human ACE2 receptor.

In a phase 1-2 double-blind, randomized, placebo-controlled study in outpatients with mild-to-moderate COVID-19, participants received either CAS/IMD 2400 mg (CAS 1200 mg/IMD 1200 mg, n = 92), CAS/IMD 8000 mg (CAS 4000 mg/IMD 4000 mg, n = 90), or placebo (n = 93) within 3 days of positive SARS-CoV-2.⁴⁷ The primary endpoint was time-weighted average change (TWA) in viral load from baseline to day 7; secondary outcomes included number of COVID-related medical visits to day 29, safety, and symptom improvement. At day 7, the TWA change in viral load was greater among those in the CAS/IMD arms compared to placebo, both in the overall trial population (−1.74 +/− .11 log10 copies/mL vs −1.34 +/− .13 log10 copies/mL; CI −1.60 to −1.08) as well as in those who were serum antibody-negative at baseline (−1.94 +/− .13 log10 copies/mL vs −1.37 +/− .20 log10 copies/mL, CI −1.76 to −.98). The combined CAS/IMD arms reported a lower number of COVID-related medical visits vs placebo: 3% vs 6% in the overall trial population and 6% vs 15% in the participants who were serum antibody-negative at baseline. Safety outcomes including hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in both arms.

Early results also suggest that CAS/IMD is effective in preventing development of symptomatic COVID-19 infection, lowering the overall infection rate, and decreasing viral load and viral shedding when administered to people exposed to a SARS-CoV-2 positive household contact. In a phase 3 study, participants received either CAS/IMD 1200 mg (CAS 600 mg/IMD 600 mg, n = 186) or placebo (n = 223) within 96 hours of a household contact’s positive SARS-CoV-2 test.⁴⁸ Eight participants (3.6%) in the placebo arm developed PCR-positive symptomatic disease compared to none in the CAS/IMD arm (OR .00; 95% CI 0-.69). Use of CAS/IMD was associated with a 48% reduction in symptomatic or asymptomatic PCR-positive infection (10/186 vs 23/223; 95% CI .20-1.12). Injection site reactions were similar in both study arms, and a similar proportion of serious adverse events (none deemed related to study treatment) was observed.

CAS/IMD is authorized by EUA for the treatment of mild-to-moderate COVID-19, who are at high-risk for progressing to severe disease and/or hospitalization.⁴⁹ This includes the same patient populations as the criteria set under BAM/ETE EUA. CAS/IMD is also not authorized for use in patients who are hospitalized due to COVID-19, require oxygen therapy or increased oxygen requirements from baseline due to COVID-19. Under the EUA, CAS/IMD should be administered as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset. Recent data showed that CAS/IMD has no change in susceptibility to various SARS-CoV-2 variants, including B.1.1.7 (UK), B.1.351 (South Africa), P.1 (Brazil), B.1.427/B.1.429 (California), or B.1.526 (New York). However, it is unknown how pseudovirus data correlate with clinical outcomes. Currently, there are insufficient data for the NIH Guidelines to recommend either for or against the use of CAS/IMD for outpatients with mild-to-moderate COVID-19.¹⁰ The IDSA Guidelines also offer no recommendations, but remark that CAS/IMD may have similar clinical benefit as BAM/ETE, but data are more limited.¹¹

CAS and IMD are administered together as a single IV infusion over at least 60 minutes via pump or gravity.⁴⁹ They are not renally excreted nor metabolized by CYP450 enzymes. Therefore, drug–drug interactions are not expected with CAS/IMD. Theoretically, there is potential for SARS-CoV-2 mAbs to interfere with immune responses induced by SARS-CoV-2 vaccines; therefore, as a precautionary measure, administration of a SARS-CoV-2 vaccine should be deferred for at least 90 days following treatment with BAM/ETE or CAS/IMD.⁵⁰

Role of Pharmacists

Although often overlooked, pharmacists are one of the frontline health care workers providing much-needed services during the COVID-19 pandemic, such as managing medication shortages, assisting with procurement of investigational agents, and maintaining continuity of care through medication dispensing and home medication delivery.^51-54 Pharmacists also have roles in ensuring appropriate use of approved and investigational agents, monitoring and reporting of adverse effects (e.g., glycemic control in patients receiving corticosteroid, monitoring of renal function and liver enzymes while on remdesivir), and identifying and managing DDIs. A retrospective DDI analysis evaluated 50 hospitalized patients with COVID-19; in this study, the mean age was 74, 61% male, mean 6 comorbidities, and an average of 10 comedications per person.⁵⁵ High rates of potential interactions were identified with dexamethasone (72.5% amber, 2% red) and TOCI (74.5% amber). In addition, 62.7% of these patients had at least 1 DDI between their comedications, with the majority associated with increased risk of drug toxicity. These findings highlight the importance of routine screening for DDIs, which pharmacists are highly trained to perform. They also serve as educators by disseminating drug information to other health care professionals and patients regarding investigational agents and educating others on emergency use authorizations.

Resources

New data on COVID-19 are emerging rapidly. Some trusted and timely resources for health care professionals include the following:

• 1. NIH and IDSA

  • a. NIH: https://www.covid19treatmentguidelines.nih.gov/
  • b. IDSA: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
  • c. COVID-19 treatment guidelines, with the intent to update frequently
• 2. COVID-19 Drug Evidence Initiative

  • a. https://cdei.ca
  • b. Provides critical appraisals of COVID-19 studies
• 3. American Society of Health-System Pharmacists COVID-19 Resource Center

  • a. https://www.ashp.org/covid-19
  • b. Provides timely resources on COVID-19, including an evidence table of COVID-19-related treatment which is updated as new data emerge
• 4. University of Liverpool COVID-19 Drug Interactions.

  • a. https://www.covid19-druginteractions.org/
  • b. Provides DDIs with investigational COVID-19 agents

Conclusion

Treatment options for management of COVID-19 disease have evolved significantly since the start of the pandemic. Dexamethasone has become the standard of care in hospitalized patients with severe or critical COVID-19 due to findings of mortality benefit in the RECOVERY trial. Remdesivir improves recovery time in hospitalized patients who require supplemental oxygen, but a mortality benefit has not been demonstrated. In the REMAP-CAP and RECOVERY trials, mortality benefits were observed with tocilizumab in combination with corticosteroids in certain hospitalized patients at risk of progression to severe decompensation. The monoclonal antibody combinations bamlanivimab/etesevimab and casirivimab/imdevimab have been granted emergency use authorizations for use in non-hospitalized patients with mild-to-moderate COVID-19 who have a high-risk of progression to severe disease.

While treatment options continue to evolve, there are still many unanswered questions including clearly identifying which agents are most effective for mild, moderate, and severe disease, optimal time for therapy initiation, ideal dosage, duration of therapy, and which combination therapy would be most beneficial. Clinicians need to critically evaluate available data, particularly since some studies have not been published or peer-reviewed, and make clinical judgment based on potential benefits vs risks on an individual basis. Pharmacists can play a role in ensuring appropriate access, correct administration, and safe use of COVID-19 treatments and are encouraged to stay abreast of new developments.

ORCID iD

Salin Nhean https://orcid.org/0000-0001-6310-2811