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Mechanistic Modeling of the Effect of Recombinant Human Hyaluronidase (rHuPH20) on Subcutaneous Delivery of Cetuximab in Rats

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Abstract

Purpose

To evaluate the duration of effect of rHuPH20 on SC absorption of cetuximab and to develop a mechanistic pharmacokinetic model linking the kinetics of rHuPH20 action with hyaluronan (HA) homeostasis and absorption of cetuximab from the SC space.

Methods

Serum pharmacokinetics of cetuximab was evaluated after IV and SC dosing at 0.4 and 10 mg/kg (control groups). In test groups, SC cetuximab was administered simultaneously with rHuPH20 (Co-Injection) or 12 h after injection of rHuPH20 (Pre-Injection). Mechanistic pharmacokinetic model was developed to simultaneously capture cetuximab kinetics in all groups.

Results

Administration of rHuPH20 resulted in a faster absorption of cetuximab; the difference between co-injection and pre-injection groups appeared to be dependent on the dose level. The model combined three major components: kinetics of rHuPH20 at SC site; HA homeostasis and its disruption by rHuPH20; and cetuximab systemic disposition and the effect of HA disruption on cetuximab SC absorption. The model provided good description of experimental data obtained in this study and collected previously.

Conclusions

Proposed model can serve as a potential translational framework for capturing the effect of rHuPH20 across multiple preclinical species and in human studies and can be used for optimization of SC delivery of biotherapeutics.

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ACKNOWLEDGMENTS AND DISCLOSURES

The study was funded, in part, by a grant from Halozyme Therapeutics Inc. to Leonid Kagan. The authors would like to thank Dr. Charvi Nanavati for scientific discussions and support of the Rutgers-Halozyme collaboration. Xizhe Gao, JongBong Lee, Kiran Deshpande, Leonid Kagan – no conflict. David W Kang - employee of Halozyme Therapeutics Inc. Anas M Fathallah – former employee of Halozyme Therapeutics Inc.

Funding

The study was supported by a research grant from Halozyme Therapeutics Inc. to Leonid Kagan.

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Authors and Affiliations

  1. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA

    Xizhe Gao, Jongbong Lee, Kiran Deshpande & Leonid Kagan

  2. Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA

    Xizhe Gao, Kiran Deshpande & Leonid Kagan

  3. Halozyme Therapeutics Inc., San Diego, California, 92121, USA

    David W. Kang & Anas M. Fathallah

Authors
  1. Xizhe Gao
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  2. Jongbong Lee
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  3. Kiran Deshpande
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  4. David W. Kang
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  5. Anas M. Fathallah
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  6. Leonid Kagan
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Contributions

Conception and design of the study – DWK, AMF, LK

Data acquisition – XG, JBL, KD

Data analysis and interpretation – XG, LK

Drafting the manuscript and critically revising – XG, LK, DWK, AMF

LK is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Leonid Kagan.

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Gao, X., Lee, J., Deshpande, K. et al. Mechanistic Modeling of the Effect of Recombinant Human Hyaluronidase (rHuPH20) on Subcutaneous Delivery of Cetuximab in Rats. Pharm Res 39, 1867–1880 (2022). https://doi.org/10.1007/s11095-022-03294-y

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  • DOI: https://doi.org/10.1007/s11095-022-03294-y

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