Novel Approach for Low-Dose Pulmonary Delivery of Hydroxychl
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The widespread use of HCQ has had unintended consequences on the healthcare system by precipitating an increased need for cardiac monitoring (due to QTc prolongation) and straining the medication's existing supply chain. Taken together, strategies that mitigate the risk CQ/HCQ-related systemic adverse effects should be pursued in the critically ill COVID-19 population.

-- As an alternative to high-dose (200-600mg) oral therapy, authors propose low-dose (10-20mg) delivery of water soluble hydroxychloroquine sulfate (HCQS) via controlled nebulization or inhalation using metering valves and commercially available metered-dose inhalers.
-- Given that the recommended maintenance dose of HCQ is 6.4mg/kg/day and that the collective weight of the lungs is ~1kg, 10-20mg/day of inhaled HCQS (equivalent to 7.7-15.7mg/day free base) is a suitable alternative to the presently utilized orally-administered dosing regimens.
-- This lower inhaled dose is possible due to the large volume of distribution (44,257 L) for orally administered HCQ.
-- When given orally, only a small fraction of the drug is delivered to the lungs, while the remainder deposits in other tissues and may cause unintended adverse effects.
-- Drug administration via nebulization allows direct delivery to lung alveoli and pulmonary tissues to elicit local effects, necessitating far lower doses than those used orally.
-- Pharmacokinetically, HCQ remains largely neutral at physiological pH and can freely diffuse into cells and lysosomes.
-- Upon encountering the acidic pH (4.5-5.0) of lysosomes, it is protonated into its ionized state, becoming membrane impermeable and effectively “trapped” in the lysosome.
-- This phenomenon greatly limits systemic exposure from inhaled or nebulized HCQ.

Therefore, if HCQ is to be administered in critically ill COVID-19 patients, low-dose inhaled or nebulized therapy may confer the collective benefits of similar or greater drug concentrations in pulmonary tissues, less systemic adverse effects (including cardiotoxicity), decreased burden on the healthcare system, and diminished strain on the existing supply of hydroxychloroquine.

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