Prediction of long-term treatment outcome in HCV following 24 day PEG-IFN alpha-2b therapy using population pharmacokinetic-pharmacodynamic mixture modeling and classification analysis.

Mathematical models have been widely used for understanding the dynamics of the hepatitis C virus (HCV). We propose a method to predict final clinical outcome for 24 HIV-HCV - coinfected patients with the help of a mathematical model based on the first two weeks of PEG-IFN therapy. Applying a pharmacokinetic-pharmacodynamic (PKPD) approach, together with mixture models, to the adapted model of viral dynamics developed by Neumann et al., we have analyzed the influence of PEG-IFN on the kinetics and interaction of target cells, infected cells and virus mRNA. It was found that PEG-IFN pharmacokinetic parameters were similar in sustained virological responders and nonresponders, while the plasma PEG-IFN concentration that decreases HCV production by 50% (EC50) and the rate of infected cell death were different. The treatment outcome depended mainly on the initial viral mRNA concentration and the rate of infected cell death. The population PKPD approach with a mixture model enabled the determination of individual PKPD parameters and showed high sensitivity (93.5%) and specificity (97.4%) for the prediction of the treatment outcome.

Modeling of celiac disease immune response and the therapeutic effect of potential drugs.

BACKGROUND: Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed people and is caused by a reaction to the gluten protein found in wheat, which leads to intestinal villous atrophy. Currently there is no drug for treatment of CD. The only known treatment is lifelong gluten-free diet. The main aim of this work is to develop a mathematical model of the immune response in CD patients and to predict the efficacy of a transglutaminase-2 (TG-2) inhibitor as a potential drug for treatment of CD. RESULTS: A thorough analysis of the developed model provided the following results:1. TG-2 inhibitor treatment leads to insignificant decrease in antibody levels, and hence remains higher than in healthy individuals.2. TG-2 inhibitor treatment does not lead to any significant increase in villous area.3. The model predicts that the most effective treatment of CD would be the use of gluten peptide analogs that antagonize the binding of immunogenic gluten peptides to APC. The model predicts that the treatment of CD by such gluten peptide analogs can lead to a decrease in antibody levels to those of normal healthy people, and to a significant increase in villous area. CONCLUSIONS: The developed mathematical model of immune response in CD allows prediction of the efficacy of TG-2 inhibitors and other possible drugs for the treatment of CD: their influence on the intestinal villous area and on the antibody levels. The model also allows to understand what processes in the immune response have the strongest influence on the efficacy of different drugs. This model could be applied in the pharmaceutical R&D arena for the design of drugs against autoimmune small intestine disorders and on the design of their corresponding clinical trials.

Regulation of leukotriene and 5oxoETE synthesis and the effect of 5-lipoxygenase inhibitors: a mathematical modeling approach.

BACKGROUND: 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes and 5-Oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (oxoETE). These inflammatory signaling molecules play a role in the pathology of asthma and so 5-LO inhibition is a promising target for asthma therapy. The 5-LO redox inhibitor zileuton (Zyflo IR/CR(®)) is currently marketed for the treatment of asthma in adults and children, but widespread use of zileuton is limited by its efficacy/safety profile, potentially related to its redox characteristics. Thus, a quantitative, mechanistic description of its functioning may be useful for development of improved anti-inflammatory targeting this mechanism. RESULTS: A mathematical model describing the operation of 5-LO, phospholipase A2, glutathione peroxidase and 5-hydroxyeicosanoid dehydrogenase was developed. The catalytic cycles of the enzymes were reconstructed and kinetic parameters estimated on the basis of available experimental data. The final model describes each stage of cys-leukotriene biosynthesis and the reactions involved in oxoETE production. Regulation of these processes by substrates (phospholipid concentration) and intracellular redox state (concentrations of reduced glutathione, glutathione (GSH), and lipid peroxide) were taken into account. The model enabled us to reveal differences between redox and non-redox 5-LO inhibitors under conditions of oxidative stress. Despite both redox and non-redox inhibitors suppressing leukotriene A4 (LTA4) synthesis, redox inhibitors are predicted to increase oxoETE production, thus compromising efficacy. This phenomena can be explained in terms of the pseudo-peroxidase activity of 5-LO and the ability of lipid peroxides to transform 5-LO into its active form even in the presence of redox inhibitors. CONCLUSIONS: The mathematical model developed described quantitatively different mechanisms of 5-LO inhibition and simulations revealed differences between the potential therapeutic outcomes for these mechanisms.

DBSolve Optimum: a software package for kinetic modeling which allows dynamic visualization of simulation results.

BACKGROUND: Systems biology research and applications require creation, validation, extensive usage of mathematical models and visualization of simulation results by end-users. Our goal is to develop novel method for visualization of simulation results and implement it in simulation software package equipped with the sophisticated mathematical and computational techniques for model development, verification and parameter fitting. RESULTS: We present mathematical simulation workbench DBSolve Optimum which is significantly improved and extended successor of well known simulation software DBSolve5. Concept of "dynamic visualization" of simulation results has been developed and implemented in DBSolve Optimum. In framework of the concept graphical objects representing metabolite concentrations and reactions change their volume and shape in accordance to simulation results. This technique is applied to visualize both kinetic response of the model and dependence of its steady state on parameter. The use of the dynamic visualization is illustrated with kinetic model of the Krebs cycle. CONCLUSION: DBSolve Optimum is a user friendly simulation software package that enables to simplify the construction, verification, analysis and visualization of kinetic models. Dynamic visualization tool implemented in the software allows user to animate simulation results and, thereby, present them in more comprehensible mode. DBSolve Optimum and built-in dynamic visualization module is free for both academic and commercial use. It can be downloaded directly from http://www.insysbio.ru.