A Novel Mechanistic and Physiologically-Based Pharmacokinetic Model with Dynamic Gastrointestinal Fluid Transport

oral absorption;mechanistic model;dissolution;Pharmacy and Pharmacology;Health Sciences;Pharmaceutical Sciences

Yu, AlexSmith, David Eric ;

University of Michigan

关键词: oral absorption;    mechanistic model;    dissolution;    Pharmacy and Pharmacology;    Health Sciences;    Pharmaceutical Sciences;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/143946/alexmyu_1.pdf?sequence=1&isAllowed=y

瑞士|英语

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

【 摘 要 】

A better understanding of the rate and extent for oral drug product dissolution in the gastrointestinal (GI) tract can provide an invaluable perspective in the drug development process. As it is difficult to experimentally measure the rate and extent of dissolution, the purpose of this research is to develop a validated model-based method that translates clinically observed plasma profiles into predictions of in vivo dissolution with validation by GI drug concentration profiles. The resulting model was based on physiologically considerations such as series-based transit, fluid volume, mucus layer, and pH to model the oral absorption process. Local GI fluid volume was identified as a poorly characterized physiological variable that essential in modeling local GI drug concentrations, thereby influencing the simulation of drug dissolution and absorption. A dynamic fluid transport model was developed from GI fluid volumes found in literature with validation based on transport of a non-absorbable marker. The simulation found volumes in the GI tract to vary more in the upper than later GI and more at earlier timepoints than later timepoints. The simulation also found faster drug transit that reflected the earlier larger volumes followed by slower transit when volume is limited, explaining the observed extended residence time of drug in the stomach and small intestine environments. To predict the rate and extent of in vivo drug dissolution, an algorithm based deconvolution of human plasma profile after 800 mg ibuprofen dose was deployed using the developed mechanistic model with the addition of a two-compartment pharmacokinetic model. Consideration of gastric emptying lag time was essential to validating the simulated and experimental in vivo GI concentration profile of ibuprofen observed in a recent clinical study where lag time was determined by rapid rise of ibuprofen in plasma that reflects its significantly higher solubility in the small intestine pH environment. The simulation predicted minimal dissolution (2%) in the stomach, rapid but short dissolution in the duodenum (6.3%), core dissolution in the jejunum (63%) over 210 minute period, and completion of dissolution in the ileum (25%).To further obtain reference data for evaluation of in vivo dissolution, a clinical study was conducted that found extended residence time mesalamine in the GI tract for modified release formulations. To model the extended residence time of mesalamine drug in the stomach, the deconvolution algorithm was applied to human plasma profile after 1000 mg dose of Pentasa using the developed mechanistic model with the addition of a two-compartment pharmacokinetic model. The characterization of bio-adherence from excipients used in the formulation was incorporated in the mechanistic oral absorption model by establishing additional mucus compartments where particles would ;;attach;; and experience slower transit due to mucus. The simulation produced local GI drug concentrations similar in magnitude to the clinically observed profiles with extended residence past 7 hours. The acquisition of local GI concentration profiles played a critical role in developing in vivo dissolution models with validation. The data further suggests that quantification of dynamic GI fluid and consideration of GI mucus can not only play an essential role in transit and absorption of solubilized drug, but also be a contributing factor to the transit and regional dissolution of drug particles. The resulting in vivo dissolution profile may be key to developing in vivo relevant in vitro dissolution studies.