P. G. Ravenstijn; Janssen Research & Development, Beerse, Belgium
BACKGROUND: Tapentadol is a strong analgesic indicated for the management of pain in adults and is currently under development for children. The objective of the PBPK modeling is to predict the exposure of Tapentadol in children down to 2 years of age. In vivo metabolism experiments showed that metabolism is mainly through glucuronidation (see figure).
METHODS: Simcyp v12.2 (Simcyp Ltd, UK) was used to develop the PBPK models of Tapentadol and O-Glucuronide. Using the retrograde model, the measured adult CLPO and CLR were used to calculate a HLM CLint, which was then allocated to the different enzymes (see figure). The physicochemical properties of the metabolite were predicted based on the chemical structure and optimized using adult data. The compound files were validated using data from adults and children < 6 years (interim data).
RESULTS: The PBPK model for Tapentadol is able to predict the adult and children 12-18 years Tapentadol and O-Glucuronide plasma concentrations. The predictions in children 6-11 years seem to slightly overpredict the observed data. The allocation of 55% of UGT contribution to the overall clearance gives a good prediction of the plasma O-Glucuronide concentrations.
CONCLUSION: The PBPK model is able predict the exposure of Tapentadol in children down to 2 years of age.