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The In Vitro, In Vivo, and PBPK Evaluation of a Novel Lung-Targeted Cardiac-Safe Hydroxychloroquine Inhalation Aerogel

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Abstract

Hydroxychloroquine (HCQ) was repurposed for COVID-19 treatment. Subtherapeutic HCQ lung levels and cardiac toxicity of oral HCQ were overcome by intratracheal (IT) administration of lower HCQ doses. The crosslinker-free supercritical fluid technology (SFT) produces aerogels and impregnates them with drugs in their amorphous form with efficient controlled release. Mechanistic physiologically based pharmacokinetic (PBPK) modeling can predict the lung’s epithelial lining fluid (ELF) drug levels. This study aimed to develop a novel HCQ SFT formulation for IT administration to achieve maximal ELF levels and minimal cardiac toxicity. HCQ SFT formulation was prepared and evaluated for physicochemical, in vitro release, pharmacokinetics, and cardiac toxicity. Finally, the rat HCQ ELF concentrations were predicted using PBPK modeling. HCQ was amorphous after loading into the chitosan-alginate nanoporous microparticles (22.7±7.6 μm). The formulation showed a zero-order release, with only 40% released over 30 min compared to 94% for raw HCQ. The formulation had a tapped density of 0.28 g/cm3 and a loading efficiency of 35.3±1.3%. The IT administration of SFT HCQ at 1 mg/kg resulted in 23.7-fold higher bioavailability, fourfold longer MRT, and eightfold faster absorption but lower CK-MB and LDH levels than oral raw HCQ at 4 mg/kg. The PBPK model predicted 6 h of therapeutic ELF levels for IT SFT HCQ and a 100-fold higher ELF-to-heart concentration ratio than oral HCQ. Our findings support the feasibility of lung-targeted and more effective SFT HCQ IT administration for COVID-19 compared to oral HCQ with less cardiac toxicity.

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Acknowledgements

The authors acknowledge Jordan University of Science and Technology (Irbid, Jordan) for all facilities and support provided. Also, the authors acknowledge ACDIMA Biocenter (Amman, Jordan) for developing the assay method and analyzing hydroxychloroquine concentration in blood samples collected from rats. Finally, the authors acknowledge Simulations Plus Inc. (Lancaster, CA, U.S.A.) for providing an academic license of GastroPlus® used to analyze the hydroxychloroquine pharmacokinetic data measured in the current study and that reported in the literature used to verify the model.

Funding

This project was funded by a local fund (grant no.: 53/2022) provided by Jordan University of Science and Technology (Irbid, Jordan).

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan

    Mo’tasem M. Alsmadi & Mays M. Jaradat

  2. Nanotechnology Institute, Jordan University of Science and Technology, Irbid, Jordan

    Mo’tasem M. Alsmadi

  3. Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, The University of Jordan, Amman, Jordan

    Rana M. Obaidat

  4. Department of Pharmaceutical and Chemical Engineering, Faculty of Applied Medical Sciences, German Jordanian University, Amman, Jordan

    Mohammad Alnaief

  5. ACDIMA Biocenter, Amman, Jordan

    Rabab Tayyem

  6. College of Pharmacy, University of Petra, Amman, Jordan

    Nasir Idkaidek

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Contributions

• Alsmadi, Jaradat, Obiadat, and Alnaief made substantial contributions to the conception and design of the work.

• Alsmadi, Jaradat, Obiadat, and Tayyem had substantial contributions to the acquisition of the data.

• Alsmadi, Jaradat, Obiadat, Alnaief, and Idkaidek had substantial contributions to the analysis and interpretation of data for the work.

• Alsmadi, Jaradat, Obiadat, and Idkaidek had substantial contributions to drafting the work and revising it critically for important intellectual content.

• All authors approved and agreed to be accountable for all aspects of the final version to be published and ensured that the questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Mo’tasem M. Alsmadi.

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Alsmadi, M.M., Jaradat, M.M., Obaidat, R.M. et al. The In Vitro, In Vivo, and PBPK Evaluation of a Novel Lung-Targeted Cardiac-Safe Hydroxychloroquine Inhalation Aerogel. AAPS PharmSciTech 24, 172 (2023). https://doi.org/10.1208/s12249-023-02627-3

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