In Silico, Experimental, Mechanistic Model for Extended-Release Felodipine Disposition Exhibiting Complex Absorption and a Highly Variable Food Interaction

Abstract

The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog’s plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability.

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…Such in silico models can decipher complex, highly variable absorption and food interaction pharmacokinetics for a modified release drug product using an object-and agent-oriented discrete event system, which maps various physiological features and processes (Kim et al, 2014). The current-day pharmaceutical industry has a huge financial interest in the inclusion of computational (in silico) analysis in early stages of drug screening.…”

Simulation Enabled Search for Explanatory Mechanisms of the Fracture Healing Process

“…Given the Fig 4 reality, that approach is not available. As explained in [21] and demonstrated in [22,23,25,27], an advantage of the software-based model mechanism approach is that, by keeping model mechanism entities parsimoniously coarse grain and concrete, we limit the variety and space of model mechanisms capable of generating the targeted phenomenon.…”

“…To do so, requires that software mechanisms responsible for the transition of Target Region from initial to final state be plausibly biomimetic. We do that by employing the same type of software mechanism used successfully in other contexts [22,25,26,27,30] while adhering to the rigorous definition of mechanism provided in S1 File.…”

“…By adhering to a strong parsimony guideline (IR Protocol step 2), we avoided adding unnecessary details; doing so enabled us to avoid inscription error. More details on overfitting and analog-to-referent mappings can be found in the Discussion section of Kim et al [25]. In the subsections that follow, we describe four workflow stages, designated Mechanisms 1-4.…”

“…The most pressing current need is to develop strategies and methods to workaround and eventually overcome each of the above four obstacles. We conjectured that the software-based model mechanism methods, which we have used successfully in other contexts (e.g., see [21][22][23][24][25][26]), could provide the foundation for such strategies, even though, for those earlier applications, considerably more mechanism related fine grain knowledge was available. Briefly stated, the cited software-based model mechanism approach begins with a target phenomenon.…”