Population level predictions of QT prolonging effects for
hydroxychloroquine and hypokalaemia
Our hiPSC-CM data suggests differences in drug effects between
individual patient lines as well as a more pronounced prolongation of
repolarisation in the context of hypokalamia. To interrogate this
further, we performed population level simulations of the cardiac action
potential to assess the variability in drug response between individual
subjects and to illustrate the consequences of the electrolyte-dependent
changes in hERG potency. In addition to the kalaemic-dependence of
potency of hydroxychloroquine against hERG measured in our assays, these
simulations also incorporate block of the inward rectifier potassium
current (IK1), the cardiac sodium current
(INa), and the cardiac L-type calcium current
(ICaL) from the literature (22). However, it should be
noted that the contribution of this multichannel pharmacology to the
overall effect on repolarisation is relatively small, since the degree
of block at the highest dose of hydroxychloroquine simulated (3000
ng/ml) were 4.1 %, 20 % and 7.3 % for ICaL,
IK1 and INa respectively, compared to 70
% block of hERG at the same concentration (see Supplementary table 2).
Populations of action potentials representing baseline (no drug, normal
electrolytes), 1000 ng/ml hydroxychloroquine and hydroxychloroquine +
mild hypokalaemia are shown in Figure 4A. Frequency distribution
histograms of repolarisation duration illustrating the effect of
hypokalaemia on population response to 1000 ng/ml and 3000 ng/ml
hydroxychloroquine (an estimate of mean plasma Cmax and
maximum plasma Cmax respectively, see Discussion) are
shown in Figure 4B-D and summarised in Figure 4E. In normokalaemia, the
time to 90 % repolarisation (APD90) was increased to
355 ± 49 ms (mean ± SD) and 4444 ± 60 ms for 1000 ng/ml and 3000 ng/ml
hydroxychloroquine respectively compared to baseline (274 ± 40 ms).
Furthermore, within these distributions, a range in the severity of
prolongation of repolarisation was observed, even for those individuals
with the same baseline APD90s (Supplementary Movie 1).
Mild hypokalaemia further increased the duration of repolarisation to
383 ± 53 ms and 481 ± 63 ms for 1000 ng/ml and 3000 ng/ml
hydroxychloroquine. The percentage of the population with
APD90 >500 ms in response to 3000 ng/ml
hydroxychloroquine increased from 17.4 % in normokalaemia to 34.8 % in
hypokalaemia, reflecting a significant increase in proarrhythmic risk
associated with mild hypokalaemia.