A New Model to Describe the Single-dose Pharmacokinetics of Bevacizumab and Predict Its Multiple-Dose Pharmacokinetics in Beagle Dogs.

Abstract

Complex pharmacokinetic (PK) properties including nonlinear elimination were encountered by some monoclonal antibodies (mAbs), and classic compartment models sometimes failed to appropriately describe those properties. In this work, a new model was built on a comprehensive analysis of the complex elimination of mAbs. This new model was firstly utilized to fit with the single-dose plasma concentration data of bevacizumab in beagle dogs receiving an intravenous administration of 2.5 mg/kg bevacizumab. Then, the optimal PK parameters from fitting with the single-dose PK data were employed into the multiple-dose mathematical expressions to predict bevacizumab’s multiple-dose PK profiles. One-compartment model recommended as the optimal classic model by DAS 2.0 software was set as a control. As a result, new model fitted better with the single-dose PK profiles of bevacizumab with smaller weighted residual sum of squares and higher fitting degree compared with the classic model. Importantly, new model also accurately predicted the multiple-dose PK profiles of bevacizumab and performed well at the single-to-multiple transition. In conclusion, the new model reasonably explained the complex elimination of bevacizumab, and it might play a big role in the PK studies of bevacizumab and other mAbs.