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Stochastic Differential Equation-based Mixed Effects Model of the Fluid Volume in the Fasted Stomach in Healthy Adult Human

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Abstract

The rate and extent of drug dissolution and absorption from a solid oral dosage form depend largely on the fluid volume along the gastrointestinal tract. Hence, a model built upon the gastric fluid volume profiles can help to predict drug dissolution and subsequent absorption. To capture the great inter- and intra-individual variability (IAV) of the gastric fluid volume in fasted human, a stochastic differential equation (SDE)-based mixed effects model was developed and compared with the ordinary differential equation (ODE)-based model. Twelve fasted healthy adult subjects were enrolled and had their gastric fluid volume measured before and after consumption of 240 mL of water at pre-determined intervals for up to 2 hours post ingestion. The SDE- and ODE-based mixed effects models were implemented and compared using extended Kalman filter algorithm via NONMEM. The SDE approach greatly improved the goodness of fit compared with the ODE counterpart. The proportional and additive measurement error of the final SDE model decreased from 14.4 to 4.10% and from 17.6 to 4.74 mL, respectively. The SDE-based mixed effects model successfully characterized the gastric volume profiles in the fasted healthy subjects, and provided a robust approximation of the physiological parameters in the very dynamic system. The remarkable IAV could be further separated into system dynamics terms and measurement error terms in the SDE model instead of only empirically attributing IAV to measurement errors in the traditional ODE method. The system dynamics were best captured by the random fluctuations of gastric emptying coefficient Kge.

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Acknowledgements

Main results were simply put together in the appendix of the PhD thesis of Kai Wang entitled with “Mechanistic Model-based Drug Oral Absorption Analysis.” Additional analysis and discussion were included in this manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Kai Wang, Gordon L. Amidon, David E. Smith & Duxin Sun

  2. Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK

    Luca Marciani

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  1. Kai Wang
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Contributions

Dr. Wang conducted the data analysis and drafted the manuscript. Dr. Marciani provided data. Dr. Marciani, Dr. Amidon, Dr. Smith, and Dr. Sun revised the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Kai Wang.

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Wang, K., Marciani, L., Amidon, G.L. et al. Stochastic Differential Equation-based Mixed Effects Model of the Fluid Volume in the Fasted Stomach in Healthy Adult Human. AAPS J 25, 76 (2023). https://doi.org/10.1208/s12248-023-00840-3

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