In silico drug absorption tract: An agent-based biomimetic model for human oral drug absorption

• Published in: PloS one 2018-08, Vol.13 (8), p.e0203361-e0203361
• Main Authors: Deng, Jianyuan, Jhandey, Anika, Zhu, Xiao, Yang, Zhibo, Yik, Kin Fu Patrick, Zuo, Zhong, Lam, Tai Ning
• Format: Article
• Language: English
• Subjects: Absorption; Administration, Oral; Agent-based models; Area Under Curve; Bioavailability; Biological Availability; Biology and Life Sciences; Biomimetics; Biomimetics - methods; Chemical properties; Clinical trials; Clonazepam; Computer and Information Sciences; Computer Simulation; Criteria; Drugs; Graphical user interface; Health aspects; Humans; Intestinal absorption; Intestinal Absorption - physiology; Kinetics; Knowledge representation; Mathematical models; Medical research; Medicine; Medicine and Health Sciences; Membranes; Metabolism; Midazolam; Models, Biological; Oral drugs; Ordinary differential equations; Parameters; Pharmaceutical Preparations - metabolism; Pharmaceutical research; Pharmaceuticals; Pharmacokinetics; Pharmacology; Pharmacy; Physical Sciences; Physiological aspects; Physiology; Reaction kinetics; Research and Analysis Methods; Similarity; Simulation; Solubility; Studies
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0203361

An agent-based modeling approach has been suggested as an alternative to traditional, equation-based modeling methods for describing oral drug absorption. It enables researchers to gain a better understanding of the pharmacokinetic (PK) mechanisms of a drug. This project demonstrates that a biomimetic agent-based model can adequately describe the absorption and disposition kinetics both of midazolam and clonazepam. An agent-based biomimetic model, in silico drug absorption tract (ISDAT), was built to mimic oral drug absorption in humans. The model consisted of distinct spaces, membranes, and metabolic enzymes, and it was altogether representative of human physiology relating to oral drug absorption. Simulated experiments were run with the model, and the results were compared to the referent data from clinical equivalence trials. Acceptable similarity was verified by pre-specified criteria, which included 1) qualitative visual matching between the clinical and simulated concentration-time profiles, 2) quantitative similarity indices, namely, weighted root mean squared error (RMSE), and weighted mean absolute percentage error (MAPE) and 3) descriptive similarity which requires less than 25% difference between key PK parameters calculated by the clinical and the simulated concentration-time profiles. The model and its parameters were iteratively refined until all similarity criteria were met. Furthermore, simulated PK experiments were conducted to predict bioavailability (F). For better visualization, a graphical user interface for the model was developed and a video is available in Supporting Information. Simulation results satisfied all three levels of similarity criteria for both drugs. The weighted RMSE was 0.51 and 0.92, and the weighted MAPE was 5.99% and 8.43% for midazolam and clonazepam, respectively. Calculated PK parameter values, including area under the curve (AUC), peak plasma drug concentration (Cmax), time to reach Cmax (Tmax), terminal elimination rate constant (Kel), terminal elimination half life (T1/2), apparent oral clearance (CL/F), and apparent volume of distribution (V/F), were reasonable compared to the referent values. The predicted absolute oral bioavailability (F) was 44% for midazolam (literature reported value, 31-72%) and 93% (literature reported value, ≥ 90%) for clonazepam. The ISDAT met all the pre-specified similarity criteria for both midazolam and clonazepam, and demonstrated its ability to describe absorption kinetics of