Testing the method of multiple scales and the averaging principle for model parameter estimation of quasiperiodic two time-scale models

summary:Some dynamical systems are characterized by more than one time-scale, e.g. two well separated time-scales are typical for quasiperiodic systems. The aim of this paper is to show how singular perturbation methods based on the slow-fast decomposition can serve for an enhanced parameter estimation when the slowly changing features are rigorously treated. Although the ultimate goal is to reduce the standard error for the estimated parameters, here we test two methods for numerical approximations of the solution of associated forward problem: (i) the multiple time-scales method, and (ii) the method of averaging. On a case study, being an under-damped harmonic oscillator containing two state variables and two parameters, the method of averaging gives well (theoretically predicted) results, while the use of multiple time-scales method is not suitable for our purposes

Biochemical network of drug-induced enzyme production: Parameter estimation based on the periodic dosing response measurement

summary:The well-known bottleneck of systems pharmacology, i. e., systems biology applied to pharmacology, refers to the model parameters determination from experimentally measured datasets. This paper represents the development of our earlier studies devoted to inverse (ill-posed) problems of model parameters identification. The key feature of this research is the introduction of control (or periodic forcing by an input signal being a drug intake) of the nonlinear model of drug-induced enzyme production in the form of a system of ordinary differential equations. First, we tested the model features under periodic dosing, and subsequently, we provided an innovative method for a parameter estimation based on the periodic dosing response measurement. A numerical example approved the satisfactory behavior of the proposed algorithm

Regulatory network of drug-induced enzyme production: parameter estimation based on the periodic dosing response measurement

summary:The common goal of systems pharmacology, i.e. systems biology applied to the field of pharmacology, is to rely less on trial and error in designing an input-output systems, e.g. therapeutic schedules. In this paper we present, on the paradigmatic example of a regulatory network of drug-induced enzyme production, the further development of the study published by Duintjer Tebbens \textit{et al}. (2019) in the Applications of Mathematics. Here, the key feature is that the nonlinear model in form of an ODE system is controlled (or periodically forced) by an input signal being a drug intake. Our aim is to test the model features under both periodic and nonrecurring dosing, and eventually to provide an innovative method for a parameter estimation based on the periodic dosing response measurement

On parameter estimation in an in vitro compartmental model for drug-induced enzyme production in pharmacotherapy

summary:A pharmacodynamic model introduced earlier in the literature for in silico prediction of rifampicin-induced CYP3A4 enzyme production is described and some aspects of the involved curve-fitting based parameter estimation are discussed. Validation with our own laboratory data shows that the quality of the fit is particularly sensitive with respect to an unknown parameter representing the concentration of the nuclear receptor PXR (pregnane X receptor). A detailed analysis of the influence of that parameter on the solution of the model's system of ordinary differential equations is given and it is pointed out that some ingredients of the analysis might be useful for more general pharmacodynamic models. Numerical experiments are presented to illustrate the performance of related parameter estimation procedures based on least-squares minimization

Advanced Computational Fluid Dynamics Study of the Dissolved Oxygen Concentration within a Thin-Layer Cascade Reactor for Microalgae Cultivation

High concentration of dissolved oxygen within microalgae cultures reduces the performance of corresponding microalgae cultivation system (MCS). The main aim of this study is to provide a reliable computational fluid dynamics (CFD)-based methodology enabling to simulate two relevant phenomena governing the distribution of dissolved oxygen within MCS: (i) mass transfer through the liquid–air interface and (ii) oxygen evolution due to microalgae photosynthesis including the inhibition by the same dissolved oxygen. On an open thin-layer cascade (TLC) reactor, a benchmark numerical study to assess the oxygen distribution was conducted. While the mass transfer phenomenon is embedded within CFD code ANSYS Fluent, the oxygen evolution rate has to be implemented via user-defined function (UDF). To validate our methodology, experimental data for dissolved oxygen distribution within the 80 meter long open thin-layer cascade reactor are compared against numerical results. Moreover, the consistency of numerical results with theoretical expectations has been shown on the newly derived differential equation describing the balance of dissolved oxygen along the longitudinal direction of TLC. We argue that employing our methodology, the dissolved oxygen distribution within any MCS can be reliably determined in silico, and eventually optimized or/and controlled

Systems biology analysis of a drug metabolism (with slow-fast. . . )

In the systems biology literature, complex systems of biochemical reactions (in form of ODEs) have become increasingly common. This issue of complexity is often making the modelled processes (e.g. drug metabolism, XME induction, DDI) difficult to intuit or to be computationally tractable, discouraging their practical use

Matematické modelování v mirořasové biotechnologii

Prezenční470 - Katedra aplikované matematikyNeuveden

REGULATORY NETWORK OF DRUG-INDUCED ENZYME PRODUCTION: PARAMETER ESTIMATION BASED ON THE PERIODIC DOSING RESPONSE MEASUREMENT

The common goal of systems pharmacology, i.e. systems biology applied to the eld of pharmacology, is to rely less on trial and error in designing an input-output systems, e.g. therapeutic schedules. In this paper we present, on the paradigmatic example of a regulatory network of drug-induced enzyme production, the further development of the study published by Duintjer Tebbens et al. (2019) in the Applications of Mathematics. Here, the key feature is that the nonlinear model in form of an ODE system is controlled (or periodically forced) by an input signal being a drug intake. Our aim is to test the model features under both periodic and nonrecurring dosing, and eventually to provide an innovative method for a parameter estimation based on the periodic dosing response measurement

Bohl-Marek decomposition applied to a class of biochemical networks with conservation properties

This study presents an application of one special technique, further called as Bohl-Marek decomposition, related to the mathematical modeling of biochemical networks with mass conservation properties. We continue in direction of papers devoted to inverse problems of parameter estimation for mathematical models describing the drug-induced enzyme production networks [3]. However, being aware of the complexity of general physiologically based pharmacokinetic (PBPK) models, here we focus on the case of enzyme-catalyzed reactions with a substrate transport chain [5]. Although our ultimate goal is to develop a reliable method for fitting the model parameters to given experimental data, here we study certain numerical issues within the framework of optimal experimental design [6]. Before starting an experiment on a real biochemical network, we formulate an optimization problem aiming to maximize the information content of the corresponding experiment. For the above-sketched optimization problem, the computational costs related to the two formulations of the same biochemical network, being (i) the classical formulation x˙(t) = Ax(t) + b(t) and (ii) the 'quasi-linear' Bohl-Marek formulation x˙M(t) = M(x(t)) xM(t), can be determined and compared