A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study

Abstract

<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, lung concentration (6.7 μg/mL) to predict the in vivo antiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 μg/g (C<jats:sub>max</jats:sub>) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher (~30-fold) lung exposure, longer (~2.5-fold) half-life in lung, but lower blood exposure with ~20% of C<jats:sub>max</jats:sub> and 74% of AUC and lower heart exposure with 24% of C<jats:sub>max</jats:sub> and 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.</jats:p>

Chloroquine and Hydroxychloroquine for the Prevention and Treatment of COVID-19: A Fiction, Hope or Hype? An Updated Review

“…With several cases overwhelming the healthcare systems, it becomes unpractical to screen all patients for the potential interactions in the clinical setting. Future directions in the CQ/HCQ drugs might include improved drug delivery either by inhalation 67 or transcatheter delivery through the bronchial artery. 68 The randomized and controlled WHO Solidarity 69 trial did not find an effectiveness of HCQ in reducing mortality rate (risk ratio of 1.19; P = 0.23) among the hospitalized COVID-19 patients.…”

Harnessing biomaterials for therapeutic strategies against COVID-19

“…Inhalation would result in local pulmonary drug delivery while minimizing adverse side effects [ 68 ]. For instance, when tested in rats, intratracheal instillation of dipalmitoylphosphatidylcholine/cholesterol liposomes encapsulating HCQ resulted in increased drug half-life and local accumulation into lung tissues with minimal off-target toxicity [ 69 ]. These biomaterials can also be used to deliver dexamethasone, a steroid used to treat patients critically ill with COVID-19 [ 56 ].…”

Current updates on adaptive immune response by B cell and T cell stimulation and therapeutic strategies for novel coronavirus disease 2019 (COVID-19) treatment

“…TLC19 uses TLC's existing proprietary liposome technology to encapsulate ~1/100 of the oral hydroxychloroquine (HCQ) dose into an inhalable formulation for direct deposit into the airways and lungs. TLC reasons that TLC19 may have an antiviral effect with a miniscule dosage relative to oral HCQ thus minimising blood and heart exposure, giving TLC19 the ability to treat COVID-19 without many of the side effects found in some trials ( Tai et al., 2020 ).…”