Pharmacology and Toxicity of 4-Aminoquinones
Hydroxychloroquine and chloroquine belong to a class of drugs known as
4-aminoquinones. Hydroxychloroquine differs from chloroquine by the
presence of a hydroxyl group at the end of the side chain.
Hydroxychloroquine has considerable pharmacokinetic variability and the
terminal half-life is 40-50 days.[3, 4] Both molecules are weak
bases and can irreversibly accumulate in acidic environments, such as
the lysosome, which contributes to its large volume of distribution and
impacts the amount of free drug available in tissues.[5] Plasma,
blood and serum concentrations can vary in individual patients and
between patients after identical doses. Hydroxychloroquine has an active
metabolite, desethylhydroxychloroquine (DHCQ) that is largely formed by
CYP3A4.[6]
The immune modulatory mechanisms of hydroxychloroquine have not yet been
fully elucidated; however, they are believed to include the reduction of
Toll-like receptor and cGAS-STING signaling, attenuation of
pro-inflammatory cytokine production, and inhibition of lysosomal
activity and autophagy.[7-9] It is unknown whether
hydroxychloroquine has a direct antiviral effect in COVID-19, and if so,
what plasma concentrations of the drug and its active metabolite are
efficacious. Antiviral effects of chloroquine against RNA viruses,
including SARS-CoV-1, have previously been demonstrated in vitroincluding alteration of cellular pH and disruption of the endolysosomal
pathway critical for viral entry, replication and assembly.[10, 11]
Similar studies of hydroxychloroquine in SARS-CoV-2 indicated similar
activity.[12, 13]
In designing our trial, we relied on a published randomized dose-ranging
trial in rheumatoid arthritis (RA), which demonstrated that a dose of
1200 mg of hydroxychloroquine daily for up to 6 weeks was safe and
achieved a more rapid response than lower daily doses.[3, 14]
Previously published pharmacokinetic studies in RA patients indicate
that the maximum concentration after the first dose is approximately
one-third of the steady-state concentration.[15] Therefore a dose of
1200 mg daily is expected to achieve concentration achievable at 400 mg
daily at steady-state, which does not occur until approximately five
times the terminal half-life of 40 days.
Shortly after our trial was initiated, physiologically based
pharmacokinetic modeling performed in vitro identified an
effective free lung tissue trough concentration/EC50 in cell culture
could be reached by hydroxychloroquine loading doses on Day 1 of
therapy, between 400 mg BID and 600 mg BID.[13] However, the U.S.
FDA cautioned interpretation of these results as the model used severely
underestimated the required intracellular EC50 for therapeutic effectin vivo. Rather, they concluded there was a low likelihood of
achieving effective in vivo concentration of hydroxychloroquine
with a safe oral regimen.[16] Subsequent pharmacokinetic/
pharmacodynamic (PKPD) modeling of pooled data from all in vitroand clinical studies of COVID-19 predicted dosing regimens of at least
800 mg/day for greater than 5 days were required to decrease viral loads
compared with dosing regimens of less than 400 mg/day.[17]
Higher dosing strategies must consider incremental toxicities of
hydroxychloroquine. Overdosage can occur with oral ingestion and include
symptoms of headache, drowsiness, visual disturbance, cardiovascular
collapse.[18] Retinal toxicity and cardiomyopathy are serious
toxicities; however are believed to represent a long-term and
dose-dependent cumulative phenomenon.[19, 20] Hydroxychloroquine is
structurally similar to the class IA antiarrhythmic quinidine, which
inhibits voltage-gated sodium and potassium channels, including the hERG
cardiomyocyte Kv11.1 channel and contributes to drug-induced QTc
prolongation and increases the risk of torsades de pointes and sudden
cardiac death.[21]
No studies have established a concentration-dependent relationship
between hydroxychloroquine and risk for QTc prolongation and most of the
data supporting concerns for QTc prolongation with hydroxychloroquine
have been based on studies of chloroquine.[22] Historical experience
evaluating QTc in patients treated with hydroxychloroquine for
rheumatologic diseases has not revealed strong association with cardiac
toxicity.[23, 24] The aforementioned trial which utilized 1200 mg
daily for 6 weeks in RA reported no difference in therapy
discontinuation and no reports of cardiovascular events up to 24 weeks
of follow up.[3, 14] In COVID-19, one model using chloroquine data
to predict risk of QTc prolongation with hydroxychloroquine estimated
that doses 400-600 BID for 10 days or less were unlikely to cause
clinically significant QTc prolongation in patients without risk factors
for QTc prolongation.[17] Recent studies evaluating QTc prolongation
in hospitalized patients with COVID-19 being treated with
hydroxychloroquine monotherapy, found a significant percentage of
patients developed a prolonged QTc of 500 milliseconds or had a change
in QTc of 60 milliseconds or more however none developed
arrhythmias.[25, 26] In these studies, 75% and 50% of patients
respectively were concomitantly taking one or more other medications
with known QTc-prolonging effects and both studies lacked a control
group.