2. Academic Validation
  3. Hyaluronidase impacts exposures of long-acting injectable paliperidone palmitate in rodent models

Hyaluronidase impacts exposures of long-acting injectable paliperidone palmitate in rodent models

  • bioRxiv. 2024 Mar 6:2024.03.03.583160. doi: 10.1101/2024.03.03.583160.
Henry Pertinez 1 2,  Amit Kaushik 3,  Paul Curley 1 2,  Usman Arshad 1 2,  Eman El-Khateeb 1 2,  Si-Yang Li 3,  Rokeya Tasneen 3,  Joanne Sharp 1 2,  Edyta Kijak 1 2,  Joanne Herriott 1 2,  Megan Neary 1 2,  Michaël Noë 4,  Charles Flexner 5,  Eric Nuermberger 3,  Andrew Owen 1 2,  Nicole C Ammerman 3 6
Affiliations

Affiliations

  • 1 Center of Excellence for Long-Acting Technologies (CELT), William Henry Duncan Building, University of Liverpool, Crown Street, Liverpool L7 8TX, UK.
  • 2 Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, William Henry Duncan Building, Crown Street, Liverpool L69 7BE, UK.
  • 3 Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD, 21287, USA.
  • 4 Department of Pathology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
  • 5 Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
  • 6 Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, Netherlands.
PMID: 38496644 DOI: 10.1101/2024.03.03.583160
Abstract

A significant challenge in the development of long-acting injectable drug formulations, especially for anti-infective agents, is delivering an efficacious dose within a tolerable injection volume. Co-administration of the extracellular matrix-degrading enzyme hyaluronidase can increase maximum tolerable injection volumes but is untested for this benefit with long-acting injectable formulations. One concern is that hyaluronidase could potentially alter the tissue response surrounding an injection depot, a response known to be important for drug release kinetics of long-acting injectable formulations. The objective of this pilot study was to evaluate the impact of co-administration of hyaluronidase on the drug release kinetics, pharmacokinetic profiles, and injection site histopathology of the long-acting injectable paliperidone palmitate for up to four weeks following intramuscular injection in mouse and rat models. In both species, co-administration of hyaluronidase increased paliperidone plasma exposures the first week after injection but did not negate the overall long-acting release nature of the formulation. Hyaluronidase-associated modification of the injection site depot was observed in mice but not in rats. These findings suggest that further investigation of hyaluronidase with long-acting injectable agents is warranted.

Keywords

histopathology; hyaluronidase; mouse model; paliperidone palmitate; pharmacokinetics; rat model.

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