Determination of the latent geometry of atorvastatin pharmacokinetics by transfer entropy to identify bottlenecks

Abstract

Abstract Background In mathematics, a physical network (e.g. biological network, social network, IT network, communication network) is usually represented by a graph. The determination of the metric space (also referred to as latent geometry) of the graph and the disposition of its nodes on it provide important information on the reaction propensity and consequently on the possible presence of bottlenecks in a system of interacting molecules, such as it happens in pharmacokinetics. To determine the latent geometry and the coordinates of nodes, it is necessary to have the dissimilarity or distance matrix of the network, an input that is not always easy to measure in experiments. Results The main result of this study is the mathematical and computational procedure for determining the distance/dissimilarity matrix between nodes and for identifying the latent network geometry from experimental time series of node concentrations. Specifically, we show how this matrix can be calculated from the transfer entropy between nodes, which is a measure of the flow of information between nodes and thus indirectly of the reaction propensity between them. We implemented a procedure of spectral graph embedding to embed the distance/dissimilarity matrix in flat and curved metric spaces, and consequently to determine the optimal latent geometry of the network. The distances between nodes in the metric space describing the latent geometry can be analyzed to identify bottlenecks in the reaction system. As a case study for this procedure, we consider the pharmacokinetics of atorvastatin, as described by recent studies and experimental time data. Conclusions The method of determining distances between nodes from temporal measurements of node concentrations through the calculation of transfer entropy makes it possible to incorporate the information of kinetics (inherent in the time series) in the construction of the distance/dissimilarity matrix, and, consequently, in the determination of the network latent geometry, a characterisation of the network itself that is intimately connected to its dynamics, but which has so far been scarcely investigated and taken into account. The results on the case study of the pharmacokinetics of atorvastatin corroborate the usability and reliability of the method within certain limits of the experimental errors on the data.