Mechanisms of Subcutaneous Absorption of Rituximab in Rats

Abstract

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 receptormediated transport is a major determinant of s.c. absorption of mAbs.

The effect of the neonatal Fc receptor on human IgG biodistribution in mice

“…This suggested that FcRn plays a role in antibody tissue distribution. Garg et al further proposed that the muscle and skin 8,9 are among the major sites of IgG catabolism, where FcRn-mediated transport from blood to tissue contributes significantly to IgG extravasation in these two tissues.…”

Interspecies Pharmacokinetic Modeling of Subcutaneous Absorption of Rituximab in Mice and Rats

“…A mathematical model has been developed to study absorption mechanisms of mAbs in rats using rituximab as a model drug (12,13). The bioavailability of rituximab following SC administration decreases inversely with the dose level, and this nonlinear behavior is assumed to manifest from saturation of FcRn-mediated protective binding at the absorption site (14).…”

Population Pharmacokinetic Modeling of LY2189102 after Multiple Intravenous and Subcutaneous Administrations

“…In support of this hypothesis, FcRndeficient mice were reported to have threefold lower bioavailability of an IgG1 antibody compared to wild-type mice (22). Similarly, increased affinity of mAbs to FcRn at pH 6.0 (akin to lysosomal pH), but not pH 7.4, was associated with greater SC bioavailability in mice (27,28), while coadministration of rituximab with IgG (and thus saturating the FcRn interaction) reduced its bioavailability in mice (29). In contrast, engineering a series of five IgG4 variants for enhanced FcRn interaction failed to consistently improve SC bioavailability in cynomolgus monkeys (30), although a trend was suggested for those associated with lower starting bioavailability.…”