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

Abstract

The airways and lungs are the primary sites of SARS-CoV-2 entry, replication, and damage, so there is reason to administer drugs to these regions. Oral hydroxychloroquine (oHCQ) has produced mixed results in COVID-19, despite reported antiviral activity in vitro (EC50=0.72-119 μM). We tested the hypothesis that aerosolized HCQ sulfate (aHCQ) tolerably, safely, and rapidly achieves high respiratory tissue concentrations, while minimizing systemic toxicity. aHCQ was administered via Aerogen nebulizer (oral inhalation, nasal exhalation) to healthy volunteers in a Phase 1 study to assess tolerability, safety, and pharmacokinetics. 10 volunteers (age 55±13 years, 60% female) were randomized to Placebo (n=2), or aHCQ (20 mg, n=2; 50 mg, n=6); all completed the inhalation. 6/8 receiving aHCQ had adverse events (all mild; 75% transient dysgeusia, 25% dizziness). FEV1 and FVC were essentially unchanged from baseline after 15-360 minutes and 1 and 7 days. QT segments were minimally changed from baseline (maximum change 34 msec) after 1-6 hours, and 1 and 7 days; all were ≤455 msec. Pharmacokinetics of 50 mg: Area Under the Blood Curve 0-24 hours post-inhalation was 377±127 ng*hr/mL, <15% of that reported for oHCQ 200 mg; Pharmacokinetic modelling predicts initial epithelial lining fluid concentrations in excess of reported EC50s, and peak respiratory tissue concentrations of 0.5 mM, decreasing to 0.01 mM at 24 hours as HCQ slowly releases into blood. aHCQ was safe, well-tolerated, and appears to be sequestered in respiratory tissues. Administering aHCQ at a fraction of oral dosing may rapidly achieve respiratory tract concentrations sufficient to inhibit SARS-CoV-2.