Identifying a predictive relationship between maximal flow rate and viscosity for subcutaneous administration of macromolecules with recombinant human hyaluronidase PH20 in a miniature pig model

Abstract

Subcutaneous (SC) infusion of large volumes at rapid flow rates has historically been limited by the glycosaminoglycan hyaluronan (HA), which forms a barrier to bulk fluid flow in the SC space. Recombinant human hyaluronidase PH20 (rHuPH20) depolymerizes HA, temporarily eliminating this barrier to rapid SC delivery of large volume co-administered therapeutics. Using a miniature pig model, in-line pressure and applied force to the delivery hardware were measured when subcutaneously infusing a representative macromolecule (human polyclonal immunoglobulin [Ig]), at varying concentrations and viscosities (20–200 mg/mL), co-formulated with and without rHuPH20 (2000 U/mL and 5000 U/mL). Maximal flow rate (Q_max) was calculated as the flow rate producing a statistically significant difference in mean applied force between injections administered with or without rHuPH20. There was a significant reduction in mean applied force required for SC delivery of 100 mg/mL Ig solution with 5000 U/mL rHuPH20 versus Ig solution alone. Similar significant reductions in mean applied force were observed for most Ig solution concentrations, ranging from 25–200 mg/mL when administered with or without 2000 U/mL rHuPH20. Q_max was inversely proportional to Ig solution viscosity and Q_max for solutions co-formulated with 5000 U/mL rHuPH20 was approximately double that of 2000 U/mL rHuPH20 solutions. Mathematical simulation of a hypothetical 800 mg Ig dose co-formulated with rHuPH20 showed that delivery times <30 s could be achieved across a broad range of concentrations. Addition of rHuPH20 can help overcome volume and time constraints associated with SC administration across a range of concentrations in a dose-dependent manner.

Keywords:

• Large volume
• maximal flow rate
• recombinant human hyaluronidase PH20
• subcutaneous
• viscosity

Acknowledgments

The authors would like to thank all investigators involved in this study, and Drs Anna-Maria Hays Putnam, Michael J LaBarre, and Stephen Knowles for reviewing the manuscript. Medical writing support, including assisting authors with the development of the outline and initial draft, and incorporation of comments, was provided by Rachel O’Meara, PhD, and editorial support was provided by Sarah Christopher, PhD, of Paragon, Knutsford, UK, supported by Halozyme Therapeutics, Inc. Halozyme follows all current policies established by the International Committee of Medical Journal Editors and Good Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M22-1460). The sponsor was involved in the study design and collection, analysis, and interpretation of data, as well as data verification of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.

Disclosure statement

RJC and DWK are employees of Halozyme Therapeutics, Inc., and hold shares in the company. RC is a former employee of Halozyme Therapeutics, Inc.

Author contribution

RJC was responsible for the conception, design, and execution of the study, as well as for interpreting the data, drafting the paper, revising it critically for intellectual content, and providing final approval of the final draft for publication.

RC was responsible for the conception, design, and execution of the study, as well as for interpreting the data, drafting the paper, revising it critically for intellectual content, and providing final approval of the final draft for publication.

DWK was responsible for the conception, design, and execution of the study, as well as for interpreting the data, drafting the paper, revising it critically for intellectual content, and providing final approval of the final draft for publication.

All authors agree to be accountable for all aspects of the work.

Data sharing statement

Halozyme Therapeutics, Inc. follows policies established by the International Committee of Medical Journal Editors and Good Publication Practice guidelines (link). The studies were conducted by Halozyme Therapeutics, Inc. and the data are held by the company. The datasets supporting the results reported in this article may be provided to researchers upon reasonable request. Such requests can be made by contacting Halozyme Therapeutics, Inc.: 12390 El Camino Real, San Diego, CA 92130, USA; Phone: [phone]; Email: [email protected].

Additional information

Funding

Development of this manuscript was supported by Halozyme Therapeutics, Inc.