Mechanistic Analysis and Quantification of Gastrointestinal Motility: Physiological Variability and Plasma Level Implications.

pharmaceutical sciences;gastrointestinal motility;oral drug product;bioequivalence;modeling;manometry;Physiology;Science;Pharmaceutical Sciences

Talattof, ArjangSun, Duxin ;

University of Michigan

关键词: pharmaceutical sciences;    gastrointestinal motility;    oral drug product;    bioequivalence;    modeling;    manometry;    Physiology;    Science;    Pharmaceutical Sciences;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/113403/arjang_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The oral route of administration is still by far the most ubiquitous method of drug delivery. Development in this area still faces many challenges due to the complex inhomogeneity of the gastrointestinal environment. In particular, gastric emptying and gastrointestinal motility is not predictable and so dosing occurs randomly with respect to these physiological variables. The goal of this research is to present a mass balance analysis that captures this variation, highlighting the effects of motility and exploring how it ultimately impacts plasma levels and the relationship to bioequivalence. A mechanistic analysis is first developed describing the underlying fasted state cyclical motility and how the contents of the gastrointestinal tract are propelled. This physiologically based approach allows the estimation of potential absorption ranges based on uncontrolled variation. Validation of the simulations is based on reported gastric emptying profiles and volumetric emptying as well as previous experimental works on gastrointestinal transit times, and the bioequivalence implications of such variation are also considered. Next, a dissolution model is presented to account for the dynamics of physiological conditions along the gastrointestinal tract, including small volumes and variable pH profiles.Predicting the extent of dissolution along with transit profiles of dissolved and particulate content is crucial to approximating absorption. Ibuprofen and phenol red are used as example cases.Finally, a method for refining the gastrointestinal transit model is critical for ensuring accuracy, and a methodology is presented for extracting relevant information from intubation studies. Gastrointestinal manometry can be thought of as a stochastic process in which the indeterminacy of state transition times belies absolute periodicity of the system. To account for this inherent randomness, the use of statistical computing can identify and characterize the different phases of the gastrointestinal cycle. Specifically, a Gaussian process is used as a robust regression method to model the time-dependent evolution of the signal. As further validation, using a pressure peak detection method based on continuous wavelet transforms and subsequently a kernel density estimator as a smoothing function, regression-based motility phase classification corresponds expected pressure peak density estimates.