Mechanisms of subcutaneous absorption of rituximab in rats.

Absorption of monoclonal antibodies (mAbs) after s.c. injection results from the interplay among several kinetic processes. The aims of this study were to investigate the absorption mechanisms of rituximab in rats by using slow s.c. infusion and coadministration with nonspecific IgG or hyaluronidase, and to evaluate the predictive performance of the pharmacokinetic model previously developed to describe the nonlinear absorption behavior of mAbs. Rituximab serum concentrations were measured after s.c. coadministration with nonspecific IgG and hyaluronidase to rats. Several dose levels and different injection sites were evaluated. For the back site, 6.5- and 2.6-fold decreases in the area under the concentration-time curve were obtained after coadministration with IgG for 1 and 10 mg/kg doses compared with administration of rituximab alone. For the abdomen, only a minor reduction in concentrations was observed. Hyaluronidase increased the rate of s.c. absorption and the bioavailability (1.9- and 1.6-fold for the back and the abdomen injection of 10 mg/kg). Our previously established pharmacokinetic model provided excellent predictions of the effect of nonspecific IgG on rituximab absorption. In conclusion, the magnitude of the effect of absorption modifiers is dependent on the site of injection and the dose level of rituximab. Pharmacokinetic profiles further support the hypothesis that neonatal Fc receptor-mediated transport is a major determinant of s.c. absorption of mAbs.