Comparison of oral absorption properties among different bisphosphonates by using a newly developed physiologically based pharmacokinetic model.

Authors: Nakai K, Nakamura M
Publication: Therapeutic Research
Software: GastroPlus®


Absorption of bisphosphonates(BPs)from the gastrointestinal tract is inhibited by forming a complex combined with multivalent cation in intake foods. Food intake other than water should be avoided for a certain period of time after oral administration of BPs to prevent the reduction of absorption. The prescribed fasting intervals vary among BPs. Object:The absorption profiles were compared among BPs by using a newly developed physiologically based pharmacokinetic (PBPK)model in order to investigate the relationship between fasting intervals and absorption profiles. Method:Alendronate(ALN), Risedronate(RIS), Minodronate (MIN)and Ibandronate(IBN)were compared in this analysis. Physiochemical properties and pharmacokinetic profiles were adopted either from the observed values in the publication or computational predicted values. Results:Serum or plasma BP concentration agreed well between the observation and the model prediction by setting paracellular pathways. Highest BP absorption was predicted in jejunum followed by duodenum and upper ileum. They were hardly absorbed in stomach, lower ileum, caecum, and ascending colon. Time to absorb more than 95% of total absorption of ALN, RIS, MIN and IBN was predicted to be about 3.5 hours. Conclusion:PBPK models for ALN, RIS, MIN and IBN were successfully developed. These models predicted absorption profiles including absorption sites and time to absorb as well as the similarity among all the BPs. It was predicted that 1 h fasting time was needed to maximize absorption. In fact, higher exposure were observed in 1 h fasting than 0.5 fasting.