Interspecies pharmacokinetic modeling of subcutaneous absorption of rituximab in mice and rats.
OBJECTIVE
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.
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA, lkagan@pharmacy.rutgers.edu.
Leonid
L
Kagan
Jie
J
Zhao
Donald E
DE
Mager
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015233:Models, Statistical; D051381:Rats; D000069283:Rituximab; D012869:Skin Absorption; D013045:Species Specificity; D065566:Subcutaneous Absorption
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab