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 (EC 50 50.72-119 mM). We tested the hypothesis that aerosolized HCQ sulfate (aHCQ) tolerably, safely, and rapidly achieves high respiratory tissue concentrations, while minimizing systemic toxicity. METHODS: aHCQ was administered via Aerogen nebulizer (oral inhalation, nasal exhalation) to healthy volunteers in a Phase 1 study to assess tolerability, safety, and pharmacokinetics. RESULTS: 10 volunteers (age 55613 years, 60% female) were randomized to Placebo (n52), or aHCQ (20 mg, n52; 50 mg, n56); all completed the inhalation. 6/8 receiving aHCQ had adverse events (all mild; 75% transient dysgeusia, 25% dizziness). FEV 1 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 3776127 ng*hr/mL, <15% of that reported for oHCQ 200 mg; Pharmacokinetic modelling predicts initial epithelial lining fluid concentrations in excess of reported EC 50 s, and peak respiratory tissue concentrations of 0.5 mM, decreasing to 0.01 mM at 24 hours as HCQ slowly releases into blood. CONCLUSIONS: 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.

Pulmonary Delivery of Aerosolized Chloroquine and Hydroxychloroquine to Treat COVID-19: In Vitro Experimentation to Human Dosing Predictions

“…An extrapolation to determine tolerable human deposited dose for pulmonary toxicity based on the surface area of the human lung (6.1 × 10 5 cm 2 ) was calculated as 14.6 g for a 24-h exposure [ 74 ]. A clinical trial involving inhaled HCQ sulfate of doses up to 50 mg/day for 7 days showed that these doses were safe and in agreement with our in vitro findings [ 75 ].…”

Nebulised Isotonic Hydroxychloroquine Aerosols for Potential Treatment of COVID-19

“…HCQS (50 µL of 100 mg/mL) aerosolised from the AERx ® Pulmonary Delivery System was studied more than a decade ago in Phase 1 and Phase 2 clinical trials for asthma treatment, owing to its anti-inflammatory properties [40]. Subjects inhaling nebulised 20 mg or 50 mg HCQS experienced only mild adverse effects (altered sense of taste and dizziness), with minimal influence on pulmonary and cardiac functions [48]. Two researchers recently self-tested the effects of inhaled hydroxychloroquine by inhaling a nebulised solution (1 mg in 2 mL of normal saline) twice a day [25].…”

“…Its atomisation mechanism is efficient, as the residual volume at the end of nebulisation is only about 50 µL [64]. This nebuliser had been used to administer HCQS to adult subjects in a recent Phase 1 pharmacokinetic study [48]. Therefore, Aerogen Solo was chosen for nebulising the HCQS solutions in the current study.…”

“…The in vivo antiviral and anti-inflammatory concentrations of hydroxychloroquine in the airways is unknown, but its in vitro antiviral EC 50 is approximately 1-5 µM, as discussed in the Introduction. After inhaling a nominal dose of 50 mg HCQS from an Aerogen nebuliser in a Phase 1 study, the peak respiratory tissue concentration was predicted by pharmacokinetic modelling to reach 500 µM, which was at least 100-fold higher than the in vitro antiviral EC 50 [48]. It decreased to 10 µM at 24 h post-inhalation but was still at least double the in vitro EC 50 .…”

“…Nebulisers can be used by patients of all ages, including those who are ventilated. Furthermore, the safety of nebulised HCQS solutions was previously demonstrated in healthy volunteers as well as subjects with pulmonary disease [40,48]. Thus, this paper reports on isotonic HCQS solutions that can be prepared, sterilised, and nebulised for potential treatment of COVID-19.…”