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

Abstract

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. Serum pharmacokinetics of cetuximab was evaluated after IV and SC dosing at 0.4 and 10mg/kg (control groups). In testgroups,SC cetuximab was administered simultaneously with rHuPH20 (Co-Injection) or 12h after injection of rHuPH20 (Pre-Injection). Mechanistic pharmacokinetic model was developed to simultaneously capture cetuximab kinetics in all groups. 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. Proposed model can serve as a potential translational framework for capturing the effect of rHuPH20 across multiple preclinical species and inhuman studies and can be used for optimization of SC delivery of biotherapeutics.