Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Hydroxychloroquine in Healthy Volunteers

Reus, Y A de; Hagedoorn, Paul; Sturkenboom, Marieke G G; Grasmeijer, Floris; Bolhuis, Mathieu S.; Sibum, Imco; Kerstjens, H.A.M.; Frijlink, Henderik W.; Akkerman, Onno W.

doi:10.1101/2020.12.03.20243162

Cited by 8 publications

(4 citation statements)

References 41 publications

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“…Extensive modelling of the PK of pulmonary administration of HCQS suggests that pulmonary administration may produce higher tissue Cmax and time above IC50 with overall low systemic exposure (59). To the best of our knowledge this is the first human aHCQS dose escalation study performed with a commercially available nebulizer (60,61).…”

Section: Assessment Of Efficacy Of It/in Hcqs In a Sars-cov-2 Hamster...mentioning

confidence: 97%

Preclinical and Human Phase 1 Studies of Aerosolized Hydroxychloroquine: Implications for Antiviral COVID-19 Therapy

Bentur

Hutt

Brassil

et al. 2023

Preprint

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Based on early reports of the efficacy of hydroxychloroquine sulfate (HCQS) to inhibit SARS-CoV-2 viral replication in vitro, and since severe pulmonary involvement is the major cause of COVID-19 mortality, we assessed the safety and efficacy of aerosolized HCQS (aHCQS) therapy in animals and humans. In a Phase 1 study of aHCQS in healthy volunteers, doses up to 50 mg were well tolerated and estimated epithelial lining fluid concentrations immediately after inhalation (>2,000 uM) exceeded the in vitro concentrations needed for suppression of viral replication (>=119 uM). A study in rats comparing HCQS solution administered orally (13.3 mg/kg) and by intratracheal installation (IT 0.18 mg/kg, <5% of oral dose) demonstrated that at 2 minutes, IT administration was associated with 5X higher mean hydroxychloroquine (HCQ) concentrations in the lung (IT: 49.5 +/- 6.5 ug HCQ/g tissue, oral: 9.9 +/- 3.4; p<0.01). A subsequent study of IT and intranasal HCQS in the Syrian hamster model of SARS-CoV-2 infection, however, failed to show clinical benefit. We conclude that aHCQS alone is unlikely to be effective for COVID-19, but based on our aHCQS pharmacokinetics and current viral entry data, adding oral HCQS to aHCQS, along with a transmembrane protease inhibitor, may improve efficacy.

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Section: Assessment Of Efficacy Of It/in Hcqs In a Sars-cov-2 Hamster...mentioning

confidence: 97%

Preclinical and Human Phase 1 Studies of Aerosolized Hydroxychloroquine: Implications for Antiviral COVID-19 Therapy

Bentur

Hutt

Brassil

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The rationale of the study was that HCQ administered as dry powder via inhalation in SARS-CoV-2 could be safer than oral HCQ, hence allowing for higher and more effective pulmonary concentrations without doseinduced toxic effects. 103,104 Further phase studies are required for inhaled aerosolized or dry powder HCQ. An ongoing study aims at developing new "Ready-to-Use" inhalable forms of HCQ that can be used directly through nebulization or using dry powder inhalers for the COVID-19 viral infection.…”

Section: Potential Of Inhaled Antiviral Therapy In Covid-19mentioning

confidence: 99%

Antivirals and the Potential Benefits of Orally Inhaled Drug Administration in COVID-19 Treatment

Sahin

Akbal-Dağıstan

Culha

et al. 2022

Journal of Pharmaceutical Sciences

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“…The following sections will focus in some detail on antivirals. [74].TLC has currently started to evaluate inhaled HCQ as liposomal formulation (TLC19) in phase 1 administered using a mesh nebulizer [75].…”

Section: The Rationale For Pulmonary Delivery Of Antiviral Drugsmentioning

confidence: 99%

Lung Delivery Systems to Optimize Pharmacotherapy of COVID-19: A Concise Review

Alrashedi

Ali

et al. 2021

JPRI

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Background: COVID-19 is an ongoing viral pandemic caused by the SARS-COV-2 virus. Several drugs were repurposed for its management; however, most of these drugs were not ideal treatments by traditional methods of administration, whether given by injection or orally. This is due to many reasons including pharmacokinetic limitations or drug-induced adverse effects. There is an urgent need to develop these drugs to target the virus in the lung tissue through inhalation. Objective: To address the gap in knowledge regarding efficacy and safety of pulmonary drug delivery of repurposed antiviral against COVID-19. Findings: Ongoing trials for inhalable formulations of several drugs such as Niclosamide; Remdesivir, Hydroxychloroquine, and Azithromycin among others showed promising results. Conclusion: The development of pharmaceutical forms for inhaled administration of antiviral and anti-inflammatory drugs is an important direction that needs more attention to achieve the optimal management of respiratory infectious diseases.

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Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Hydroxychloroquine in Healthy Volunteers

Cited by 8 publications

References 41 publications

Preclinical and Human Phase 1 Studies of Aerosolized Hydroxychloroquine: Implications for Antiviral COVID-19 Therapy

Preclinical and Human Phase 1 Studies of Aerosolized Hydroxychloroquine: Implications for Antiviral COVID-19 Therapy

Antivirals and the Potential Benefits of Orally Inhaled Drug Administration in COVID-19 Treatment

Lung Delivery Systems to Optimize Pharmacotherapy of COVID-19: A Concise Review

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