Study Of The Correlation Of Dissolution And Pharmacokinetics Of Telmisartan Tablets And The Effect Of The Gastric PH On The Pharmacokietics

Objective:To compare the dissolution of three telmisartan formulations (Brand A, Generic B, Generic C) manufactured by three different companies and their bioavailability in normal male Sprague-Dawley (SD) rats. Also to investigate the effect of increased intragastric pH on the absorption of each formulation in model rats and then establish a physiologically based pharmacokinetic model which can be used to extrapolate the in-vivo pharmacokinectics of telmisartan product by using its dissolution profile and some basic information of telmisartan.Methods:The dissolution rates of the three formulations were compared in four media:pH1.2, pH4.5, pH7.5and water using Chinese Pharmacopoeia apparatus II method (paddle method). The blood was taken from the orbit of SD rats after a single dose and a multi-dose telmisartan after they were given saline or ranitidine for seven days (80mg/kg, i.p., bid). The concentration of telmisartan in the plasma was determinated by using HPLC. The Simcyp solfware was used for the modeling.Results:Except in pH1.2, the dissolution profiles of Generic B in other three media were similar to that of the Brand (0<f1<15,50<f2<100). On the other hand the profiles of Generic C were not similar to that of the Brand in all the media used in the study. Generic C showed a rapid dissol-ution rate only under acidic conditions with a cumulative release of more than90%; but the cumulative telmisartan release was less than5%in the other three media. The results of the pharmacokinetic parameters after single dose of three telmisartan formulations in normal SD rats showed that there was no significant difference of Cmax and AUC0→72betweeen Generic B and the Brand, but a significant difference between Generic C and the Brand was observed. Increasing intragastric pH by giving ranitidine to the rats did not alter the pharmacokinetics of a single dose of the Brand and Generic B. However the increased intragastric pH significantly decreased the absorption of Generic C; whose Cmax and AUC0→72were also significantly different to that of the Brand. The multi-dose results corresponded well with the single-dose results. The modeling extrapolation results showed that the ratio of the Cmax,and AUC0→72of the virtual data and extrapolation, range between80%and120%, except for the the ratio of AUC0→72of Generic C which was69.91%. Nontheless all the modeling results for t1/2did not simulate well, the ratio was from140%to200%.Conclusions:1. Generic B whose dissolution and pharmacokinetics were close to the brand showded a better quality than Generic C.2. The in vivo variation of pharmacokinetics of Generic C with pH corresponded well with the variation of the in vitro dissolution rate which also showed pH dependence.3. pH7.5solution can reflect the quality of the generics, which can be used to as the criteria of Chinese Pharmacopoeia.4. Using the model, the in vitro dissolution profiles can be used to predict the pharmacokinetics of a telmisartan product, which means the dissolution profiles can somewhat reflect the in vivo performance of the product.