Individualized, discrete event, simulations provide insight into inter- and intra-subject variability of extended-release, drug products

Abstract

ObjectiveDevelop and validate particular, concrete, and abstract yet plausible in silico mechanistic explanations for large intra- and interindividual variability observed for eleven bioequivalence study participants. Do so in the face of considerable uncertainty about mechanisms.MethodsWe constructed an object-oriented, discrete event model called subject (we use small caps to distinguish computational objects from their biological counterparts). It maps abstractly to a dissolution test system and study subject to whom product was administered orally. A subject comprises four interconnected grid spaces and event mechanisms that map to different physiological features and processes. Drugs move within and between spaces. We followed an established, Iterative Refinement Protocol. Individualized mechanisms were made sufficiently complicated to achieve prespecified Similarity Criteria, but no more so. Within subjects, the dissolution space is linked to both a product-subject Interaction Space and the GI tract. The GI tract and Interaction Space connect to plasma, from which drug is eliminated.ResultsWe discovered parameterizations that enabled the eleven subject simulation results to achieve the most stringent Similarity Criteria. Simulated profiles closely resembled those with normal, odd, and double peaks. We observed important subject-by-formulation interactions within subjects.ConclusionWe hypothesize that there were interactions within bioequivalence study participants corresponding to the subject-by-formulation interactions within subjects. Further progress requires methods to transition currently abstract subject mechanisms iteratively and parsimoniously to be more physiologically realistic. As that objective is achieved, the approach presented is expected to become beneficial to drug development (e.g., controlled release) and to a reduction in the number of subjects needed per study plus faster regulatory review.

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

“…We adapted the in silico, whole body, drug disposition M&S framework from a previous study [5] . The framework illustrated in Fig.…”

“…In our earlier study, simple, in silico mechanisms consisting of four structures–dissolution, GI, interaction space, and plasma–sufficed for generating varied, multi-peak plasma concentration outcomes that matched individual plasma profiles of drug X from a bioequivalence study [5] . Felodipine disposition characteristics are different, but the basic processes and general, subject physiology are assumed to be similar between the two studies, which allowed us to begin by adopting the earlier analog.…”

“…Previously we introduced prototypal, biomimetic, in silico analogs for gaining insight into subject-by-formulation mechanisms that contribute to intra- and interindividual variability observed in the disposition of an extended-release oral dosage formulation of a Biopharmaceutics Classification System (BCS) Class I drug [5] . By analogs we mean executable software instantiations of plausible generative mechanisms that produce (simulate) behaviors and outcomes that mimic aspects of targeted phenomena (e.g., human drug exposure) [6] , [7] .…”

“…Given differences between BCS Class I (high solubility and high permeability) and II (low solubility, high permeability) compounds, our expectation was that mechanism changes may be needed to enable the analogs to achieve new validation targets, i.e., generate disposition specific measurements that match the felodipine plasma concentration profiles (hereafter, plasma profiles) as determined by prespecified similarity criteria. To that end we followed an iterative M&S protocol [5] , [13] , [14] to parsimoniously revise the earlier analog. Several mechanistic variants were explored, subjected to validation, and falsified.…”

Agent‐based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity

“…Amigoni and Schiaffonati, An et al, and Edelman et al provide biomedically‐focused reviews. Several applications exemplify the expanding variety of applications relevant to the pharmaceutical sciences …”