Limitations
In the absence of detailed pharmacokinetic and pharmacodynamic studies
in COVID-19 patients, plasma concentrations corresponding to the doses
of hydroxychloroquine and chloroquine that are currently undergoing
evaluation in clinical trials were best estimates based on existing
literature in other patient groups. Similarly, the concentration of
azithromycin used in our study, while corresponding to the reported
plasma Cmax, does not take into account the possibility
of tissue accumulation in patients, potentially underestimating the
degree of hERG block and hence proarrhythmic risk. Since the initial
completion of this work, other chemical entities have shown antiviral
activity against SARS-CoV2 in vitro , including 90 positive hits
from the Prestwick chemical library (50). This study is therefore not an
exhaustive analysis of small molecules that could be trialled for
treatment of COVID-19. However, it represents, to our knowledge, the
most comprehensive in vitro dataset for how hERG-related
proarrhythmia can be modified by disease associated factors and as such
provides a new blueprint for high throughput in vitro analysis of
disease associated proarrhythmic risk.