Purpose
Göttingen minipigs are increasingly being utilized to assess the pharmacokinetic (PK) properties of drug candidates due to the physical similarity with human, accessibility to all of dosing routes used in
Humans and less concern on ethics and cost. However, the accuracy of human PK prediction using Göttingen minipig data remains unknown. Therefore, the applicability of Göttingen minipigs to predict human PK profiles was investigated in this work.
Methods
We evaluated the PK parameters of 30 compounds with diverse metabolic pathways after intravenous administration in minipigs. CLtotal and Vd(ss) were predicted using single-species allometry based on the data from minipig. The predictability was compared with those from monkey, human liver chimeric mouse, and rats.
Results and Discussion
For plasma-based Vd(ss) predictions, the minipig model was not as accurate as the monkey or human liver chimeric mice models, but more accurate than the rat model. The correction of Vd(ss) using fup values did not improve the predictability of human Vd(ss).
For plasma-based CLtotal.p, the prediction accuracy of the minipig model was worse than monkeys or human liver chimeric mice models and better than the rat model. However, after correction using Rb value, for blood-based clearance (CLtotal.b), minipigs showed similar prediction accuracy to monkey and human liver chimeric mice. Notably, the prediction of CLtotal.b for non-UGT substrates using minipigs were superior to monkeys or human chimeric mice, and the percentages of compounds within 3-fold error are 84.2%, 63.2% and 72.2% for minipigs, monkeys and chimeric mice respectively.
Conclusion
The results demonstrated that when evaluating the CLtotal with Rb correction , Göttingen minipig can be used as an optional model as it represented equivalent prediction accuracy comparing with monkey or human liver chimeric mice. Furthermore, it could be a better model than monkey and chimeric mice for non-UGT substrates because of higher prediction accuracy. This study demonstrated the utility of Göttingen minipig as an animal model for CLtotal prediction.