Mathematical modeling in autoimmune diseases: from theory to clinical application.

The research & development (R&D) of novel therapeutic agents for the treatment of autoimmune diseases is challenged by highly complex pathogenesis and multiple etiologies of these conditions. The number of targeted therapies available on the market is limited, whereas the prevalence of autoimmune conditions in the global population continues to rise. Mathematical modeling of biological systems is an essential tool which may be applied in support of decision-making across R&D drug programs to improve the probability of success in the development of novel medicines. Over the past decades, multiple models of autoimmune diseases have been developed. Models differ in the spectra of quantitative data used in their development and mathematical methods, as well as in the level of "mechanistic granularity" chosen to describe the underlying biology. Yet, all models strive towards the same goal: to quantitatively describe various aspects of the immune response. The aim of this review was to conduct a systematic review and analysis of mathematical models of autoimmune diseases focused on the mechanistic description of the immune system, to consolidate existing quantitative knowledge on autoimmune processes, and to outline potential directions of interest for future model-based analyses. Following a systematic literature review, 38 models describing the onset, progression, and/or the effect of treatment in 13 systemic and organ-specific autoimmune conditions were identified, most models developed for inflammatory bowel disease, multiple sclerosis, and lupus (5 models each). ≥70% of the models were developed as nonlinear systems of ordinary differential equations, others - as partial differential equations, integro-differential equations, Boolean networks, or probabilistic models. Despite covering a relatively wide range of diseases, most models described the same components of the immune system, such as T-cell response, cytokine influence, or the involvement of macrophages in autoimmune processes. All models were thoroughly analyzed with an emphasis on assumptions, limitations, and their potential applications in the development of novel medicines.

Tyrosine phosphorylation of recombinant hirudin increases affinity to thrombin and antithrombotic activity.

Thrombin is one of the key enzymes of the blood coagulation system and a promising target for the development of anticoagulants. One of the most specific natural thrombin inhibitors is hirudin, contained in the salivary glands of medicinal leeches. The medicinal use of recombinant hirudin is limited because of the lack of sulfation on Tyr63, resulting in a 10-fold decrease in activity compared to native (sulfated) hirudin. In the present work, a set of hirudin derivatives was tested for affinity to thrombin: phospho-Tyr63, Tyr63(carboxymethyl)Phe, and Tyr63Glu mutants, which mimic Tyr63 sulfation and Gln65Glu mutant and lysine-succinylated hirudin, which enhance the overall negative charge of hirudin, as well as sulfo-hirudin and desulfo-hirudin as references. Using steered molecular dynamics simulations with subsequent umbrella sampling, phospho-hirudin was shown to exhibit the highest affinity to thrombin among all hirudin analogs, including native sulfo-hirudin; succinylated hirudin was also prospective. Phospho-hirudin exhibited the highest antithrombotic activity in in vitro assay in human plasma. Taking into account the modern methods for obtaining phospho-hirudin and succinylated hirudin, they are prospective as anticoagulants in clinical practice.

A tutorial for model-based evaluation and translation of cardiovascular safety in preclinical trials.

Assessment of drug-induced effects on the cardiovascular (CV) system remains a critical component of the drug discovery process enabling refinement of the therapeutic index. Predicting potential drug-related unintended CV effects in the preclinical stage is necessary for first-in-human dose selection and preclusion of adverse CV effects in the clinical stage. According to the current guidelines for small molecules, nonclinical CV safety assessment conducted via telemetry analyses should be included in the safety pharmacology core battery studies. However, the manual for quantitative evaluation of the CV safety signals in animals is available only for electrocardiogram parameters (i.e., QT interval assessment), not for hemodynamic parameters (i.e., heart rate, blood pressure, etc.). Various model-based approaches, including empirical pharmacokinetic-toxicodynamic analyses and systems pharmacology modeling could be used in the framework of telemetry data evaluation. In this tutorial, we provide a comprehensive workflow for the analysis of nonclinical CV safety on hemodynamic parameters with a sequential approach, highlight the challenges associated with the data, and propose respective solutions, complemented with a reproducible example. The work is aimed at helping researchers conduct model-based analyses of the CV safety in animals with subsequent translation of the effect to humans seamlessly and efficiently.

Optimization of the MACE endpoint composition to increase power in studies of lipid-lowering therapies-a model-based meta-analysis.

Aims: To develop a model-informed methodology for the optimization of the Major Adverse Cardiac Events (MACE) composite endpoint, based on a model-based meta-analysis across anti-hypercholesterolemia trials of statin and anti-PCSK9 drugs. Methods and results: Mixed-effects meta-regression modeling of stand-alone MACE outcomes was performed, with therapy type, population demographics, baseline and change over time in lipid biomarkers as predictors. Randomized clinical trials up to June 28, 2022, of either statins or anti-PCSK9 therapies were identified through a systematic review process in PubMed and ClinicalTrials.gov databases. In total, 54 studies (270,471 patients) were collected, reporting 15 different single cardiovascular events. Treatment-mediated decrease in low density lipoprotein cholesterol, baseline levels of remnant and high-density lipoprotein cholesterol as well as non-lipid population characteristics and type of therapy were identified as significant covariates for 10 of the 15 outcomes. The required sample size per composite 3- and 4-point MACE endpoint was calculated based on the estimated treatment effects in a population and frequencies of the incorporated events in the control group, trial duration, and uncertainty in model parameters. Conclusion: A quantitative tool was developed and used to benchmark different compositions of 3- and 4-point MACE for statins and anti-PCSK9 therapies, based on the minimum population size required to achieve statistical significance in relative risk reduction, following meta-regression modeling of the single MACE components. The approach we developed may be applied towards the optimization of the design of future trials in dyslipidemia disorders as well as in other therapeutic areas.