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Naji, M. |
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Motta, Antonella |
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Aletan, Dirar |
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Mohamed, Tarek |
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Ertürk, Emre |
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Taccardi, Nicola |
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Kononenko, Denys |
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Petrov, R. H. | Madrid |
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Alshaaer, Mazen | Brussels |
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Bih, L. |
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Casati, R. |
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Muller, Hermance |
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Kočí, Jan | Prague |
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Šuljagić, Marija |
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Kalteremidou, Kalliopi-Artemi | Brussels |
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Azam, Siraj |
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Ospanova, Alyiya |
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Blanpain, Bart |
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Ali, M. A. |
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Popa, V. |
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Rančić, M. |
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Ollier, Nadège |
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Azevedo, Nuno Monteiro |
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Landes, Michael |
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Rignanese, Gian-Marco |
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Am, Fathallah
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article
Mechanistic Modeling of the Effect of Recombinant Human Hyaluronidase (rHuPH20) on Subcutaneous Delivery of Cetuximab in Rats.
Abstract
<h4>Purpose</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.