A physiologically based pharmacokinetic(PBPK)model of asenapine maleate was developed and verified with the oral cavity compartmental absorption and transit(OCCAT)model and advanced compartmental absorption and transit(ACAT)model of GastroPlus™ software combined with the results of pharmacokinetic study of sublingual films in Beagle dogs.The parameter sensitivity analysis was used to quantify the effects of aqueous solubility and in vitro dissolution(Z-factor value)of asenapine maleate on the bioavailability of asenapine maleate sublingual films,and the in vivo dissolution and absorption behaviors were also simulated and predicted.The results indicated that there were delayed absorption and back-diffusion in oral transmucosal absorption of asenapine maleate.The changes in solubility and dissolution did not have significant influences on the oral transmucosal absorption when the solubility was greater than 6.2 mg/mL and the in vitro dissolution in water at 2 min was more than 70％.Based on the mechanistic analysis and prediction of the PBPK model,it was concluded that the solid dispersion technology in the preparation process of asenapine maleate sublingual films could be simplified.The results of pharmacokinetics in Beagle dogs showed that there were no statistical differences in AUC0→∞(P=0.869),cmax(P=0.902)and tmax(P=0.356)values between the sublingual films obtained before and after the process change.As a result,the PBPK modeling and simulation of asenapine sublingual films could be helpful to establish solubility and in vitro dissolution specifications and then be employed to guide drug research and development and support simplification of the preparation process.
sublingual filmphysiologically based pharmacokinetic modelasenapine maleateoral transmucosal absorption
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