Pharmacokinetic /Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19

Abstract

Tocilizumab is one of few treatments that have been shown to improve mortality in patients with COVID-19, but increased demand has led to relative global shortages. Recently, it has been suggested that lower doses, or fixed doses, of tocilizumab could be a potential solution to conserve the limited global supply while conferring equivalent therapeutic benefit to the dosing regimens studied in major trials. The relationship between tocilizumab dose, exposure, and response in COVID-19 has not been adequately characterized. There are a number of pharmacokinetic (PK) parameters which likely differ between patients with severe COVID-19 and patients in whom tocilizumab was studied during the FDA approval process. Likewise, it is unclear whether a threshold exposure is necessary for tocilizumab efficacy. The safety and efficacy of fixed versus weight-based dosing of tocilizumab has been evaluated outside of COVID-19, but it is uncertain if these observations are generalizable to severe or critical COVID-19. In the current review, we consider the potential advantages and limitations of alternative tocilizumab dosing strategies. Leveraging PK models and simulation analyses, we demonstrate that a fixed single dose of tocilizumab 400 mg is unlikely to produce PK exposures equivalent to those achieved in the REMAP-CAP trial, though weight-stratified dosing appears to produce more uniform exposure distribution. Data from current and future trials could provide PK/PD insight to better inform dosing strategies at the bedside. Ultimately, rational dosing strategies that balance available limited supply with patient needs are required.

Efficacy of tocilizumab in the treatment of COVID‐19: An umbrella review

“…One article was not accessible and thus it was excluded. 19 After evaluating the other 92 articles for eligibility, 42 were excluded for the following reasons: one study investigated tocilizumab combined with another IL‐6 inhibitor, 20 two discussed therapies other than tocilizumab, 21 , 22 37 were not systematic reviews, 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 and two were systematic reviews of preclinical or animal studies. 60 , 61 Finally, 50 articles met the eligibility criteria and were included in the present umbrella review 6 , 28 , 62 , 63 , 64 , 65 ,…”

Treatment of the cytokine storm in COVID-19: review of clinical pharmacology

“…The first is linear clearance (CL), which occurs through proteolytic degradation. The second pathway involves target engagement, such as the binding of tocilizumab to IL-6R, followed by internalization and intracellular degradation [122].…”