Prediction of population risk profile
hERG potency screens, such as that described above, are a mandated
requirement during preclinical safety screening (40). However these
screens only give an overall indication of proarrhythmic risk (41). The
severity of any given individual’s response to QT prolonging drugs is
dependent on their specific genetic background since variability in
expression of rhythmonome genes between individuals can alter their
‘repolarisation reserve’ capacity, making them more or less susceptible
to drug-induced arrhythmias (42). To predict the extent and variability
of response to the hERG block we have measured for hydroxychloroquine,
we integrated our ion channel screen data into population level
simulations of action potentials from individuals with different genetic
backgrounds. This approach allows us to both derive a quantitative
indication of population risk, as well as assess how the changes in
potency that occur as a result of electrolyte imbalance shift the
population risk. Our data show that concentrations of hydroxychloroquine
relevant to COVID-19 are predicted to cause significant prolongation of
repolarisation. Moreover, the range of responses within the population
is broad, with some individuals displaying repolarisation times in the
normal range, even in response to the highest doses of
hydroxychloroquine, while at the other tail of the population, some
individuals are predicted to be at high risk, with repolarisation times
>500 ms (a threshold chosen since QTc > 500 ms
is associated with significantly increased risk of life-threatening
cardiac events (43). Of potential significant to management of these
patients, a normal APD90 was not necessarily predictive
of the severity of prolongation of repolarisation observed in the
presence of drug. Rather, there are many combinations of genetic
background that give rise to the same baseline phenotype, that respond
differently to hERG block, depending on their repolarisation reserve.
This is consistent with the observation that some patients showing the
most pronounced QT prolongation after treatment with hydroxychloroquine
had normal QT at baseline (5) emphasising the need for longer term QTc
monitoring. The simulations also demonstrate how even mild hypokalaemia
can shift the population risk profile. For example, a reduction in
potassium of 0.5 mM (from 5 mM to 4.5 mM) increased the mean
APD90 of the population in the context of 3000 ng/ml
hydroxychloroquine by an additional 40 ms and increased the number of
individuals with repolarisation times in the high risk range
(>500 ms) from 17% to 35%. Overall, our population
simulations largely reflect recent data from cohort studies that report
similar variability and extent of response (5), thus supporting the
utility of the model for population risk prediction, particularly in the
context of COVID-19 associated risk factors.