Analysis of Nifedipine Absorption from Soft Gelatin Capsules Using PBPK Modeling and Biorelevant Dissolution Testing

Delayed absorption of nifedipine when administered as a 20mg immediate release soft gelatin capsule to fasted volunteers has been reported. Physiologically based pharmacokinetic (PBPK) modeling and in vitro dissolution data were used to explore our hypothesis that at high doses of nifedipine it precipitates in the stomach. Plasma concentration-time profiles following different doses of nifedipine were simulated using commercial PBPK software and compared to in vivo data. In vitro dissolution tests were performed with Adalat® 10mg capsules in different volumes of fasted state simulated gastric fluid (FaSSGF). The discrepancy in plasma concentration-time profiles between the different nifedipine doses could be well simulated, assuming protracted dissolution for the 20mg dose. Nifedipine release from one Adalat® 10 capsule in 250 or 500mL FaSSGF was completed within 15min whereas when release from two capsules, corresponding to 20mg nifedipine, was studied in 250mL FaSSGF, a maximum of about 75% drug dissolved was observed after 15min followed by a decline in the % dissolved to a final value of approximately 40%. Based on the in silico and in vitro results it can be concluded that the observed prolongation in nifedipine absorption following the 20mg dose was likely caused by nifedipine precipitation in human stomach.