Evaluation of the Effects of Animal Growth and Previous Exposure on the Pharmacokinetics of Rituximab in Rats.

With a long half-life, pharmacokinetic (PK) evaluation of monoclonal antibodies in rodents lasts multiple weeks during which the animals may grow significantly. We evaluated the impact of weight, age, and previous drug exposure on the PK of rituximab. Serum concentrations of rituximab were measured after intravenous and subcutaneous dosing in Sprague Dawley rats aged between 7 and 21 weeks and weighing between 200 and 600 g. The growth of rats during the study was incorporated into the model through the increase of the volumes of compartments in relation to the rats total body weight. The final model successfully captured all the data; and no difference was observed in the rituximab PK profiles between exposure naïve and redosed or young and older rats. Incorporating the rodent growth over the time course of the study into the PK model was shown to be important for providing a more physiological description of the disposition of rituximab, especially when young and rapidly growing animals are used. Redosing the same rats with monoclonal antibodies might be a viable strategy for reducing the use of laboratory animals in accordance with the 3R principles.