Hydroxychloroquine and chloroquine block hERG at doses relevant
to COVID-19.
Recent in vitro studies demonstrated EC50s for
inhibition of viral replication at 24/48 hours of 0.72 µM/6.14 µM for
hydroxychloroquine (1) and suggested that these concentrations could be
achieved with a dosing regimen of 2 X 400 mg loading/2 X 200 mg daily.
However, other trials have proposed significantly higher dosing. For
example, the Norwegian arm of the WHO’s SOLIDARITY trial had a dosing
regimen of 2 X 800 mg loading and then 2 X 400 mg daily (24). Based on
Phase I trials in patients with melanoma this would be expected to
result in an average peak blood Cmax of 2000-3000 ng/ml,
with some patients reaching 4000–6000 ng/ml (25). Assuming
~50 % serum protein binding (26), this would correspond
to an average peak plasma Cmax of 1000-1500 ng/ml
(3–4.5 µM) but up to 4000–6000 ng/ml (6-9 µM) in extreme cases. In
comparison, our analysis showed IC50 values for hERG
block of 3.7 µM for hydroxychloroquine at physiological temperature
(Figure 1).
For chloroquine, Yao et al. measured an EC50, for
inhibition of viral replication at 24/48 hours, of 5.47 µM/23.9 µM and
suggested that these concentrations could be reached with a daily 500 mg
dose (1). Various PK/PD studies broadly support this with 450 mg daily
dose for three days yielding a median Cmax of 376 µg/L
(1.2 µM) in one study (27) and long term 500 mg daily dose shown to
equilibrate to >10 µM plasma concentration (equal to
~3000 µg/L) in a second study (28). However, initial
guidelines issued for use of chloroquine in COVID-19 patients
recommended twice this dose (29) and this is reflected in proposed
trials (30). For comparison, we measured IC50 for hERG
block of 1.5 µM for chloroquine (Figure 1). Together, these data suggest
significant hERG block, and hence proarrhythmic risk, at doses relevant
to COVID-19. For example, a plasma Cmax of
~ 3 µM (a realistic estimate for either drug based on
the above), would cause 43 and 67 % block of hERG for
hydroxychloroquine and chloroquine. This use case therefore falls well
short of the 30 – 45 fold safety margins (Cmax:hERG
IC50) that have been proposed as a safe threshold in
preclinical assays (31, 32). Furthermore, our analysis does not take
into account that both chloroquine and hydroxychloroquine have been
reported to accumulate in the heart (33), meaning cardiac hERG channels
could be exposed to much higher concentrations. Our data therefore
support the conclusion that chloroquine and hydroxychloroquine carry
cardiac safety liabilities that are of significant concern at the doses
being proposed for treatment of COVID-19.