Supervisors info:
Ευάγγελος Δ. Καραλής, Αναπληρωτής Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Summary:
Thromboembolic disorders are arguably a leading cause of death worldwide, with ischemic heart disease and stroke collectively accounting for one in four deaths worldwide. This condition makes it necessary to constantly research and develop new drugs with anticoagulant properties, but also to further examine the anticoagulant drugs already available to the population. Clinical studies are conducted daily in order to study the behavior of these drugs in the human body with the aim of always achieving the best therapeutic effect. However, both the continuous sampling, which inevitably leads to the suffering of the volunteers, and the extensive financial costs from the national or international health care systems, pose the need to develop new methods for the advancement of pharmaceutical research.
In silico techniques as a scientific term correspond to the already known terms in vivo and in vitro, with the difference that they are used to describe experiments that are developed and tested in computational frameworks, describing physiological and pharmacological real conditions with the use of documented mathematical models. These computational techniques find application in clinical studies, replacing patients with virtual ones, whose pharmacokinetic parameters, such as the volume of distribution or the clearance of each drug, are drawn from the existing, documented literature. Thus it becomes possible
to create groups of virtual patients with an extent according to the desire of the researchers, without the
usually slow stage of recruitment being a counter-regulatory factor. By reducing the time, cost and inconvenience of volunteers, ISCTs present significant benefits with their advisory role in daily clinical practice.
Thus three anticoagulant drugs were selected from the three main classes of available anticoagulant medication, warfarin, vitamin K antagonist, apixaban, newer oral anticoagulant, and fondaparinux, a parenterally factor Xa antagonist, and the necessary pharmacokinetic parameters exhibited by the real
population were extracted for each of these drugs separately. The pharmacokinetic parameters collected
related to healthy populations as well as populations with gradations in age, weight as well as with numerous pathological scenarios, such as renal or hepatic impairment.
The parameters were entered into the Simulx computer program, where by applying standard deviations for each parameter, the groups of virtual patients of 100 individuals were created for each pathological or non-pathological scenario where we examined and who were administered dosage regimens of each drug based on daily clinical practice and the applicable bibliography. Plots of drug concentration in the blood of the virtual patients over time were generated which were ultimately compared between the healthy and the numerous pathological scenarios studied, in such a way that blood drug levels remained within therapeutic levels throughout the whole duration of the treatment and to achieve the best possible restoration of the patients health.
Keywords:
Anticoagulants, in silico clinical trials, Vitamin K Antagonists, Non-Vitamin K Oral Anticoagulants, factor Xa inhibitors, Warfarin, Apixaban, Fondaparinux
