Drug Shortage
Corey Diamond, PharmD
Many health systems have been caught off-guard by a sharp plunge in drug availability due to the unforeseen demand of certain medications created by the COVID-19 pandemic. Chief among them is Tocilizumab (TCZ), a monoclonal antibody interleukin-6 (IL-6) receptor antagonist that is FDA-approved for the treatment of refractory rheumatologic disorders, as well as severe or life-threatening cytokine release syndrome (CRS) from hematological cancer treatment.
What are hospitals and health systems supposed to do to try to conserve the existing supply of this antibody?
Positive outcomes of several TCZ randomized controlled trials (e.g., RECOVERY, REMAP-CAP, COVACTA, EMPACTA, et al.), and the emergency use authorization of TCZ by FDA in June 2021 led to a sudden and unanticipated surge in demand for the I.V. form of TCZ (ACTEMERA).
Optimizing the dose
Due to a dearth of practical evidence, hospitals are erring on the side of caution and using weight-based dosing for COVID-19 patients receiving TCZ, similar to that used for CRS.
Although it may vary across different institutional protocols, in general, TCZ is recommended as a single 8 mg/kg I.V. infusion within 24 hours of requiring enhanced oxygen support (e.g., mechanical ventilation, ECMO, high flow nasal canula, BiPAP). However, there are some pharmacokinetic data to suggest that alternative dosing strategies could be used to conserve the limited supply. Additionally, these strategies may retain, or even improve, the therapeutic benefit of TCZ.
In a pharmacokinetic study published by Shetty and colleagues in Drug Design, Development and Therapy in 2014, TCZ at lower dosages exhibited selective inhibition of IL-6’s pro-inflammatory receptor. In contrast, at higher dosages, TCZ prevented both IL-6’s pro-inflammatory and anti-inflammatory receptors. Based on these findings, lower dosages of TCZ could optimize the antibody’s anti-inflammatory effects and minimize interruption of its other pathways that are important for fighting viral infection.
Additionally, findings from Del Valle and colleagues, published in Nature Medicine in August 2020, showed that the IL-6 storm seen in COVID-19 patients is much smaller compared to that of traditional CRS, suggesting the labeled 8 mg/kg may be overkill for the level of inhibition required to fight COVID-19 infections.
Optimizing the waste
A pharmacokinetic study by Bastida and colleagues from 2018 published in the British Journal of Clinical Pharmacology found that in rheumatoid arthritis patients, a fixed dose of TCZ, rather than the labeled, weight-based dose, resulted in more consistent drug exposure across different patient weight groups. This begs the question of whether this strategy could translate to COVID-19 patients as well.
While it isn’t always feasible to stock several different dosage vials of a drug in a hospital pharmacy; considering TCZ is supplied in 80 mg, 200 mg, and 400 mg single-use vials, hospitals will often need to discard unused TCZ. For example, a hospital that is only supplied with 400 mg vials will need to discard half of one vial in order to prepare a 600 mg dose. Waste would be reduced if a fixed 400 mg dose was adopted rather than a weight-based approach.
Alternative agents
Sarilumab is a promising alternative substitute for TCZ, as it is a monoclonal antibody that also inhibits the IL-6 receptor and has also been studied in COVID-19 patients. The caveat is that the data are less robust, and it is unknown whether sarilumab provides patients with a similar degree of benefit.
Another treatment option includes using the subcutaneous formulation of TCZ. There are concerns, however, about such a formulation delivering similar efficacy. The subcutaneous route allows for slower absorption into the systemic circulation and has a lower peak concentration level. Additionally, there is no emergency use authorization for the subcutaneous formulation of TCZ and its use is considered off-label. However, some research has suggested similar pharmacokinetics when diluting the suspension concentrate formulation in normal saline for I.V. infusion, although there is lack of evidence for any clinical efficacy.
Currently, there are several clinical trials further evaluating these alternative agents and dosing strategies. If the outcomes are positive, it may be feasible to implement them into practice. Until then, hard ethical decisions regarding the allocation of TCZ will have to be made. ■