Fig 1.
Workflow of the rabbit PBPK/TK model development.
Starting with a generic mammalian PBPK model on top, rabbit specific physiology parameters are added (first level). Next, physicochemistry from a compound (second level), followed by information regarding active processes (third level) are introduced from literature, in-house experiments or transferred from other species. Lastly, PK data are used to identify additional parameter values of the model (fourth level).
Fig 2.
a: Generic model structure implemented in the PK-Sim® software suite. b: The sub-compartments of the tissues and the distribution scheme for the case of small molecules (RBC: red blood cells), c: The sub-compartments of the tissues and the distribution scheme for the case of large molecules.
Fig 3.
Simulations of the concentration profiles of inulin in venous blood plasma, heart, muscle, bone, lung, and skin, for 200 mg/kg intravenous administration in New Zealand white rabbits weighing 2.5 kg.
The dotted lines represent the predicted profiles, while the solid lines show the simulated profiles after the GFRspecific, skin’s hydraulic conductivity (K), and lung’s fraction interstitial (fint) were adjusted. The green dots are experimental observations from [34].
Table 1.
Comparison of experimentally observed AUC, predicted AUC, and AUC after parameter optimization for available compartments, along with the relative errors, administration details and references.
Inulin simulation efficiently described the data adopted from [37] and as such no further optimization was performed.
Fig 4.
Plasma concentration profiles of three different formulations of 50 mg paracetamol in rabbit.
The green dots are data from [38], the dotted lines are the model predictions, and the solid lines represent simulations after parameter adaption. GET: Gastric emptying time (for solution/rapidly disintegrating tablet/conventional tablet). DT: dissolution time (for rapid tablet/conventional tablet). DS: dissolution shape (for rapid tablet/conventional tablet).
Fig 5.
Local sensitivity analysis showing the ten most sensitive parameters for i.v. and p.o. (PO) administration regarding the change in AUC and Cmax.
ESAEF stands for Effective Surface Area Enhancement Factor. Upper panel shows sensitivity indices values for AUC variation, and the lower panel sensitivity indices values for Cmax variation.