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

Abstract

Purpose To investigate the effect of dose level and anatomical site of injection on the pharmacokinetics of rituximab in mice, and to evaluate the utility of a pharmacokinetic model for describing interspecies differences in subcutaneous absorption between mice and rats. Methods Rituximab serum concentrations were measured following intravenous and subcutaneous administration at the back and abdomen of mice. Several approaches were compared for scaling model parameters from estimated values in rats. Results The bioavailability of rituximab following subcutaneous injection was inversely related to the dose level and was dependent on the site of injection in mice. The overall rate of absorption was faster in mice as compared to rats. Subcutaneous absorption profiles were well described using the proposed structural model, in which the total receptor concentration, the affinity of rituximab to the receptor, and the degradation rate constant were assumed to be species independent. Conclusions Subcutaneous absorption processes show similar trends in rats and mice, although the magnitude differs between species. A mathematical model that combines the absorption of free and bound antibody with presystemic degradation successfully captured rituximab pharmacokinetics in both species, and approaches for sharing and scaling parameters between species were identified.

Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

“…Slower rates of absorption may lead to greater degradation of insulin at the injection site, resulting in a lower Cmax [59,60]. In preclinical studies conducted in rodent and sheep models [64][65][66][67], SC injection at inter-digital sites, the foot, and foot pads showed higher macromolecular SC absorption/bioavailability when compared to SC injection at the lower back, the shoulder, and the abdominal region. In humans, the depth and nature of the SC space is known to vary with anatomical location, race, age, gender, body mass index (fat composition), pigmentation, and smoking habits [68,69].…”

Challenges in the Pharmacokinetics of Therapeutic Proteins

“…Half-life was shortest in the two youngest age groups (2-and 10-days old) and increased slightly in older groups until the age of 21 days. The half-life of AMG589 in 70 day old mice (9 days) was also comparable to that observed for rituximab (8 days) [105] and other mouse IgG1s (9 days) [106] in mice.…”

“…However, a potentially lower bioavailability occurring in neonates is difficult to mechanistically explain due to many potential factors, such as the thickness of skin and lymphatic supply at the injection site, which might have influenced the absorption process [8,26]. CL/F and V/F of AMG589 in 70 day old mice were comparable to those of rituximab (CL 13.8 mL/day/kg and Vss 156 mL/kg) after IV administration at 40 mg/kg in male C57BL/6J mice (average weight 18 22 g) [105]. Terminal half-lives ( z) were the same in both datasets and ranged from 7 14 days.…”

“…The drug disposition processes of AMG589 are most likely regulated by common factors and mechanisms for mAbs, such as their large size, charge, the degree and nature of glycosylation, and the Fc region [6,55,101,105]. In many cases, mAb elimination is dominated by affinity for the FcRn receptor and their susceptibility to proteolysis.…”

Hematopoietic cells as site of first-pass catabolism after subcutaneous dosing and contributors to systemic clearance of a monoclonal antibody in mice

“…32 The high bioavailability in mice lacking hFcRn in RRC is also inconsistent with conclusions from modeling of SC absorption of rituximab in standard mice, where a contribution from receptor-medi- ated transport, i.e., transcytosis presumably via FcRn, was postulated. 33,34 Moreover, reported data in mice suggest only a very low lymphatic absorption of the SC administered bevacizumab. 35 Reconciliation of these studies with our findings in support of FcRn-dependent first-pass catabolism by HC might be explained by differences in experimental paradigms, including antibodies tested, human vs mouse FcRn, or sites of administration.…”