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.