Safety of inhaled ivermectin as a repurposed direct drug for treatment of COVID-19: A preclinical tolerance study
Introduction SARS-CoV-2 replication in cell cultures has been shown to be inhibited by ivermectin. However, ivermectin's low aqueous solubility and bioavailability hinders its application in COVID-19 treatment. Also, it has been suggested that best outcomes for this medication can be achieved via direct administration to the lung.
Objectives This study aimed at evaluating the safety of a novel ivermectin inhalable formulation in rats as a pre-clinical step.
Methods Hydroxy propyl-β-cyclodextrin (HP-β-CD) was used to formulate readily soluble ivermectin lyophilized powder. Adult male rats were used to test lung toxicity for ivermectin-HP-β-CD formulations in doses of 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg for 3 successive days.
Results The X-ray diffraction for lyophilized ivermectin-HP-β-CD revealed its amorphous structure that increased drug aqueous solubility 127-fold and was rapidly dissolved within 5 s in saline. Pulmonary administration of ivermectin-HP-β-CD in doses of 0.2, 0.4 and 0.8 mg/kg showed dose-dependent increase in levels of TNF-α, IL-6, IL-13 and ICAM-1 as well as gene expression of MCP-1, protein expression of PIII-NP and serum levels of SP-D paralleled by reduction in IL-10. Moreover, lungs treated with ivermectin (0.2 mg/kg) revealed mild histopathological alterations, while severe pulmonary damage was seen in rats treated with ivermectin at doses of 0.4 and 0.8 mg/kg. However, ivermectin-HP-β-CD formulation administered in doses of 0.05 and 0.1 mg/kg revealed safety profiles.
Conclusion The safety of inhaled ivermectin-HP-β-CD formulation is dose-dependent. Nevertheless, use of low doses (0.05 and 0.1 mg/kg) could be considered as a possible therapeutic regimen in COVID-19 cases.
The COVID-19 pandemic is arguably the world's most serious health epidemic and the biggest threat since second World War. Currently, available protocols for managing COVID-19 patients depends mainly on supporting patients, alleviating symptoms and preventing respiratory and other organ failures. Although remdesivir, received Food and Drug Administration (FDA) authorization for treatment of hospitalized COVID-19 patients, there are currently no other specific therapies approved by the FDA or this indication. Thus, the world is in great need of developing novel medications or repurposing (repositioning) of existing ones for other therapeutic application in order to develop safe and efficient treatments for COVID-19. Numerous previously available medications used as treatments for malaria (chloroquine and hydroxychloroquine) SARS-CoV (lopinavir and ritonavir) influenza viruses (favipiravir and oseltamivir) virus C hepatitis (ribavirin and sofosbuvir) and helminth/parasitic infections (ivermectin) were tested for treatment of COVID-19 .
Ivermectin an FDA-approved antiparasitic drug that is used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies has demonstrated an excellent safety profile. Ivermectin is a mysterious multifaceted 'wonder' drug that keeps shocking and exceeding expectations . It was repositioned as cancer drug and showed potent antiviral activity against Zika HIV-1 and dengue viruses. Ivermectin was reported to inhibit the replication of SARS-CoV-2 in cell cultures possibly through an RNA-dependent RNA polymerase (RdRp)-ivermectin complex, which is recognized as the most possible target for the in-vitro anti SARS-CoV-2 activity of ivermectin , thus inhibiting coronavirus replication and transcription inside the host cell . Noteworthy, available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are much argued. Some authors reported that effective concentrations are not likely attainable in humans and suggested that the required plasma concentrations necessary for the antiviral efficacy as detected in-vitro requires the administration of 100-fold the doses approved for use in humans due to its poor solubility and bioavailability While others reported that ivermectin achieves lung concentrations over 10-fold higher than its reported EC50 Despite the fact that ivermectin tends to accumulate in lung tissue, expected systemic plasma and lung tissue concentrations are much lower than the in-vitro calculated half-maximal inhibitory concentration (IC50) against SARS-CoV-2 (~2 µM) . SARS-CoV-2-induced lung inflammation or injury could further greatly affect the ability of ivermectin to accumulate in the lung cells due to changes in the pulmonary microenvironment by inflammation provoked alterations in body temperature, enzymatic activity, and pH . Hence, the advantages of lung accumulation for ivermectin may be hampered during treatment of severe SARS-CoV-2 infection
The usage of ivermectin in the management of COVID-19 is controversial. Literature existing pharmacokinetic and pharmacodynamic data show that SARS-CoV-2 inhibitory concentrations for ivermectin are not possibly achievable in humans due to its poor solubility and bioavailability , . Hence, its use in higher doses may be associated with many systemic adverse events. The present work aimed, on one hand, to prepare a HP-β-CD lyophilized readily soluble ivermectin formulation and, on the other hand, to assess the effect of intratracheal administration of this formulation on biochemical and histopathological changes in the lungs. It is postulated that ivermectin inhaled formulation is effective in SARS-CoV-2 infections. Hence, assessment of the risk–benefit profile of inhaled ivermectin is obliged .
Ivermectin-hydroxy propyl-β-cyclodextrin lyophilized formulation was prepared in 1:200 wt ratio. The lyophilized ivermectin formulation showed 127 and 30-fold increase in drug solubility compared to drug alone and drug in the physical mixture, respectively. Ivermectin X-ray diffraction patterns changed from crystalline pattern for pure drug to amorphous pattern for lyophilized formulation which revealed fast dissolution of the lyophilized powder.
This study also demonstrated the safety of different doses of inhaled ivermectin formulation with recommendation that lower doses namely, 0.05 and 0.1 mg/kg can be used as a potential treatment for COVID-19. Moreover, the current work was the first to show the probable deleterious impacts of higher doses of inhaled ivermectin (0.2, 0.4 and 0.8 mg/kg) on the lungs. This could be partially attributed to increased inflammatory and profibrotic states, as well as distorted lung architecture. The value of ivermectin in COVID-19 cases, however, requires further investigations to prove its risk/benefit profile.
Credited to Elsevier