In vitro-in silico framework for evaluating intra-subject variability in the oral absorption of BCS class 1 drugs...

The intensity of gastric peristaltic motility and the rate of gastric emptying exert a substantial influence on the gastrointestinal absorption of orally administered drugs, particularly on the rate of absorption. The objective of this study was to elucidate how these factors influence drug absorption and to establish a simple framework for predicting the variability in oral drug pharmacokinetics. To minimize inter-subject confounding, this study focused on the intra-subject variability (CV_intra) of the maximum plasma concentration (C_max). Tablets of acetaminophen (AA) and bisoprolol fumarate (BP), which are Biopharmaceutics Classification System (BCS) class 1 drugs, were used as model formulations because of their high (AA: 27.61%) and low (BP: 6.38%) CV_intra of C_max in the previously reported bioequivalence (BE) studies. This framework was designed to perform repeated in silico simulations to evaluate the impact of the Gastric Interdigestive Migrating Motor Complex (gastric IMMC) phases at the time of drug administration on its plasma concentration, based on the in vitro disintegration-driven drug release rate. The drug release rate during gastric IMMC phases I-III was evaluated using a disintegration tester in vitro. In the simulation, gastric IMMC phases at the time of administration were randomly selected based on the reported phase durations. The simulated CV_intra of C_max values were 6.47% for AA and 1.22% for BP, respectively, reproducing the rank order of variabilities in the reported BE studies. Although the absolute CV_intra values were underestimated by about fourfold, the results suggest that gastric motility and emptying partially contribute to the CV_intra of C_max. Sensitivity analyses further indicated that drug permeability and elimination-related pharmacokinetic parameters also influenced the magnitude of CV_intra of C_max, suggesting the importance of a relative balance between the absorption and distribution/elimination rates from the systemic circulation. This approach demonstrates the potential to predict the risk of intra-subject variability in oral absorption and may support formulation development of oral drug products by ensuring BE.