Individualized in vitro and in silico methods for predicting in vivo performance of enteric-coated tablets containing a narrow therapeutic index drug.

The efficacy of narrow therapeutic index (NTI) drugs is closely related to their plasma concentration-time profile. Particularly for these compounds interindividual variability of gastrointestinal (GI) parameters relevant to in vivo drug release may result in fluctuations of the plasma concentration. The present study focused on assessing the influence of individual GI pH- and transit profiles on drug release of enteric valproate tablet formulations by means of individualized in vitro dissolution experiments. After initial experiments simulating GI passages in average healthy adults, a novel in vitro dissolution model was used to simulate individual GI pH- and transit profiles with physiologically relevant dissolution media. Based on the dissolution profiles obtained in these experiments, individual in silico plasma profiles were generated and compared to fasted in vivo data applying a mean Euclidean distance approach. Simulated individual gastric residence time was identified as crucial parameter determining the onset of absorption, whereas the shape of the plasma profile is mainly influenced by individual valproate pharmacokinetics. The novel in vitro and in silico methods used in this study are promising tools for estimating in vivo drug release and plasma concentration in individual subjects and thus may contribute to a prospective risk assessment for NTI formulations.