Digitalizing the TIM-1 Model Using Computational Approaches─Part Two: Digital TIM-1 Model in GastroPlus

Abstract

A TIM-1 model is an in vitro gastrointestinal (GI) simulator considering crucial physiological parameters that will affect the in vivo drug release process. The outcome of these experiments can indicate the critical bioavailability attributes (CBAs) that will impact the fraction absorbed in vivo. The model is widely used in the nonclinical stage of drug product development to assess the bioaccessible fraction of drugs for numerous candidate formulations. In this work, we developed a digital TIM-1 model in the GastroPlus platform. In a first step, we performed validation experiments to assess the luminal concentrations and bioaccessible fractions for two marker compounds. The digital TIM-1 was able to adequately reflect the luminal concentrations and bioaccessible fractions of these markers under different prandial conditions, confirming the appropriate integration of mass transfer in the TIM-1 model. In a second set of experiments, a case example with PF-07059013 was performed, where luminal concentrations and bioaccessible fractions were predicted for 200 and 1000 mg doses under fasted and achlorhydric conditions. Experimental and simulated data pointed out that the achlorhydric effect was more pronounced at the 1000 mg dose, showing a solubility-limited dissolution and, consequently, decreased bioaccessible fraction. Toward future applications, the digital TIM-1 model will be thoroughly applied to explore a link between in vitro and in vivo outcomes based on more case examples with model compounds with the access of TIM-1 and plasma data. Ideally, this digital TIM-1 can be directly used in GastroPlus to explore an in vitro−in vivo correlation (IVIVC) between the fraction dissolved (digital TIM-1 settings) and the fraction absorbed (human PBPK settings).

Computer modeling of digestive processes in the alimentary tract and their physiological regulation mechanisms: closing the gap between digestion models and in vivo behavior

“…The first steps have been undertaken to couple in vitro digestion modeling by the TIM-1 gastrointestinal model ( 28 , 29 ) to PK/PD computer modeling ( 30 ) in order to make the in vitro modeling conditions more dynamic, recognizing that many physiological conditions vary in time and adjust to the content of the gastrointestinal compartments. In a recent development, the in vitro part of the modeling has also been incorporated in a digitized form into a GastroPlus-based modeling program ( 31 ).…”