Since discovering the airways and lungs are the primary sites of SARS-CoV-2 entry, replication, and damage researchers have attempted to administer and test drugs in these regions for efficacy.

However, trials testing oral hydroxychloroquine (oHCQ) have produced mixed results, despite having some antiviral activity in vitro (EC50­ = 0.72-119 microliters).

A team, led by Ohad Bentur, The Rockefeller University, tested the hypothesis that aerosolized HCQ sulfate (aHCQ) is tolerable, safe, and rapidly achieves high respiratory tissue concentrations while minimizing systemic toxicity.

The Trial

In the phase 1 study, aHCQ was administered with an Aerogen nebulizer to healthy volunteers to assess the overall tolerability, safety, and pharmacokinetics.

Overall, there were 10 volunteers randomized to receive either a placebo (n = 2) or aHCQ (20 mg, n = 2; 50 mg, n = 6).

All 10 patients completed the inhalation, while 6 of the 8 HCQ patients had adverse events, all of which were mild (75% transient dysgeusia; 25% dizziness).

The researchers found FEV1 and FVC were essentially unchanged from baseline after 15-360 minutes and 1 and 7 days, while QT segments were minimally changed from baseline (maximum change 34 msec) after 1-6 hours and 1 and 7 days, all of which were < 455 msec.

Pharmacokinetics of 50 mg—Area Under the Blood Curve 0-24 hours post-inhalation was 377 + 127 ng* hr/mL, while less than 15% of the patients reported for oHCQ 200 mg.

In addition, pharmacokinetic modeling predicted initial epithelial lining fluid concentrations in excess of reported EC50s, and peak respiratory tissue concentration of 0.5 mM, decreasing to 0.01 mM at 24 hours as HCQ slowly releases into the blood.

“aHCQ was safe, well-tolerated, and appears to be sequestered in respiratory tissues,” the authors wrote. “Administering aHCQ at a fraction of oral dosing may rapidly achieve respiratory tract concentrations sufficient to inhibit SARS-CoV-2.”

Mixed Results

Hydroxychloroquine was 1 of the first potential drugs tested for efficacy against COVID-19.

Late last year, researchers found in a study of 479 patients hospitalized with respiratory symptoms of COVID-19, the treatment ultimately did not improve clinical outcomes.

In the study, patients were assigned to receive hydroxychloroquine or a placebo, with 242 in the group assigned to receive 400 mg of hydroxychloroquine twice daily for 2 doses, then 200 mg twice daily for 8 doses, and 237 assigned to receive a placebo.

They were assessed 14 days after randomization based on a 7-point scale ranging from death to discharge. No significant difference was reported between the two groups (median [interquartile range] score, 6 [4-7] vs 6 [4-7]; adjusted odds ratio, 1.02 [95% confidence interval, 0.73 to 1.42]). At 28 days, 25 patients in each group (10.4% of the hydroxychloroquine group and 10.6% of the placebo group) had died.

The study, “Phase 1 Randomized Placebo-Controlled Study in Healthy Adult Volunteers to Evaluate the Safety, Tolerability, and Pharmacokinetics of Orally Inhaled Aerosolized Hydroxychloroquine Sulfate – A Potential Treatment for COVID-19,” was published online by AAAAI 2021.

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