Physiologically Based Pharmacokinetic Models for Trastuzumab Using Serial Concentrations Meausred By Optical Imaging in Mouse

Aims: Trastuzumab is a monoclonal antibody that is mainly used to treat breast cancer and exerts its therapeutic effect by inhibiting the HER2/neu receptor. The purposes of the present study were to measure the serial herceptin concentrations within each mouse after intravenous administration of trastuzumab by optical imaging, and construct physiologically based pharmacokinetic (PBPK) models for trastuzumab. By doing so, we tried to show the potential utility of nonlinear mixed effect modeling and optical imaging in pre-clinical PK evaluation.

Methods: Five serial trastuzumab concentrations (0.5, 2, 4, 6, 24 hour) in whole blood (30 μL in each) within each of 15 mouse were meaured using validated optical imaging after intravenous injection of trastuzumab, 334 μg (n=3) or 200 μg (n=12). At 24 hour after dosing, liver, lung, spleen, and kidney were enucleated and the concentrations were meaured using optical imaging. The blood and the other organ concentration data were analyzed by PBPK model implemented in NONMEM (version 7.3). In the PBPK model, volume of and blood flow to each organ were obtained from literature, and blood to organ partition coefficients were estimated. To examine the potential utility of nonlinear mixed effect PK modeling analysis using 5 serial concentration data within each animal which was possible by optical imaging, compared to conventional naïve pooled data analysis using only one concentration data within each animal, simulation study with 1,000 replicates was conducted using NONMEM.

Results: PBPK model were developed successfully from the blood and the other organ concentration data. Visual predictive check plots showed that the model predict the concentration reasonably well. In the simulation study, modeling analysis using 5 serial concentration data estimated better than that using 1 concentration. Especially, analysis using 5 data overwhelmed that using 1 datum in the reproducibility. Result of the current study suggests the potential utility of optical imaging which makes it possible to measure serial blood concentration within small, experimental animal such as mouse, in preclinical PK evaluation of drug under development in synergy with nonlinear mixed effect modeling analysis.


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