Development of a Physiologically-based Model with a regulatory and excitable cardiovascular system

  • The cardiovascular system (CVS) is an organ system that is often considered to be a closed loop system. Closed loop systems have the blood closed at all times within vessels of different size and wall thickness. The CVS consists of the heart (cardio) and the blood vessels (vascular). The CVS is responsible for the supplementation of all organs with for example nutrients and oxygen and also for the distribution of drugs throughout the body. Biological processes in the CVS are responsible for the regulation of temperature, nutrient transport, detoxification, supply with oxygen, regulation of acidity and the transport of proteins and cells of the immune system. With an impairment of this organ not only the whole CVS is disturbed, but all organs will be affected. The development of drugs, regulating the cardiovascular system (CVS) by the pharmaceutical industry is of high relevance, because cardiovascular disease (CVD) is a global epidemic [1]. There is a need for development of effective drugs in a cost reducing manner and a need to increase clinical development success rates. “Approximately one development path in ten (10.4%) that enters clinical development in phase 1 is expected to advance to FDA approval”. Especially “cardiovascular drugs had the lowest LOA (likelihood of approval) from phase 1 at 8.7% (n = 318)” [2]. To get a better knowledge about relevant processes and to support decision making in drug development, modeling and simulation techniques are well accepted and very potent methods. One of these methods is the use of physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PD) models. The pharmacokinetics describes the time course of drug absorption, distribution, metabolism, and excretion, while pharmacodynamics refers to the relationship between drug concentration at the site of action and the resulting effect. In the field of cardiovascular modeling, the PD effects can be biochemical and physiological effects like changes in hormone and enzyme levels, blood pressure or heart rate changes. PBPK models are based on a mechanistic understanding of processes, physiology and drug properties. That enables it to assess and predict the drug concentration profiles in plasma and in different organs. This knowledge is essential for an efficient drug development, because it supports a detailed understanding where the drug reaches therapeutically or even toxically concentrations. Or in other terms that is essential to understand the efficacy and risk for adverse effects of the drug in the body. PBPK models are recently used to address both, the distribution of the drug after administration, the targeted effect and all related processes. The current state of research in CV modeling reveals several approaches for this field of interest. On the one hand, there exist models describing the CVS in terms of blood flow and blood pressure and their regulation by hormonal systems like the renin-angiotensin- aldosterone system (RAAS). On the other hand there are PBPK models describing the PK of drugs all over the body. Nevertheless there is a lack of mechanistic models coupling both approaches to show the effects of PK and PD on the CVS. Up to now PBPK models representing the blood flow for the different organs are available, but no relation to blood pressure and its regulatory processes have been made. The outline and workflow of this thesis is shown in Figure 1. The thesis integrates a cardiovascular model into a whole body (wb) PBPK model to establish a mechanistic representation of the regulatory character of CVS under different physiological and pathological conditions. A main regulator of the CVS, the renin-angiotensin-aldosterone system (RAAS) was developed and coupled to the CVS to show its effects on the blood pressure. Furthermore, the coupling of the CVS to the RAAS led to a mechanistic representation of the PBPK-PD relationship. Two PBPK models for the exemplary drugs enalapril (Ena) and amlodipine have been established and the effect of these drugs on the RAAS and the CVS could be shown. Both drugs validate the PK and PD relationship within this unistructural model. Figure 1 represents an overview of the workflow. First a PBPK model for intravenous Enaat was established. This model includes physicochemical and physiological data and was evaluated with human PK-data. Then a PBPK-PO (peroral) model for Ena was created, including the respective physiological and physicochemical properties. After an evaluation with experimental PK-profiles, those two models were coupled to one model that is able to represent the PK-profile on Enaat after an oral Ena administration. Represent in a consistent manner. Then a RAAS-PD model for healthy individuals was established in a second step. After validation of the RAAS model by human data it was coupled to the Ena-Enaat model. A full PD model for the regulation of CVS was developed. It includes physiological and physical information about the CVS and represents the dynamic behavior of the blood pressure, heart rate and blood flow in a detailed organ structure. This model is a full PBPK-model and includes physiological data about hormone levels, enzyme kinetics and physicochemical properties of hormones. A PD model for the human CVS was developed, including physiological and physical information about the CVS. It was tested for some pathological states like hypertension and the Irukandji syndrome, which are indicated in Figure 1 by their own orange boxes. The CVS was evaluated with experimental PD-profiles (for the heart rate, the blood pressure or the pressure-volume relationship) for healthy individuals and then coupled to the full Ena-Enaat-RAAS-model. Finally an IV model for amlodipine was created with physicochemical and physiological data concerning amlodipine. From this a PO model for amlodipine could be evaluated, by including the respective data for amlodipine absorption, distribution, metabolism and excretion (ADME). The PO model for amlodipine was then coupled to the CV-model for healthy and also foe hypertensive individuals. Models are checked for consistency amongst each other several times. The pathogenic state of hypertension can be shown by the CV model. Finally the condition of Carukia Barnesi envenomation has been tested. The physiologically based PD model of the CVS is able to represent the basic behavior for an envenomation sufficiently well, indicating a reasonable description of the underlying physiological processes. Furthermore, a first concept for the changes in blood pressure (BP), heart rate (HR) and activity of the autonomic nervous system are shown. This model allows a more systematic approach of the CVS. This model allows for a better and more comprehensive understanding of the pharmacokinetic and the pharmacodynamics behavior of a drug acting on the CVS. Since there are no modeling approaches combining full PBPK models with full mechanistic approaches including RAAS and related effects on the CVS, this model provides a significant step further towards a better prediction of pharmacokinetic (PK) and pharmacodynamic (PD) simulations and would allow predictions in healthy and impaired conditions. It reveals the effects of blood pressure modulating drug treatments on the CVS and their own PK and PD. Thereby this model provides a further step to contribution in the process of target validation, proof of concept, dose finding and personalization of medicine.

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Publishing Institution:IRC-Library, Information Resource Center der Jacobs University Bremen
Granting Institution:Jacobs Univ.
Author:Karina Blei
Referee:Tobias Preusser, Marc-Thorsten Hütt, Michael Block
Advisor:Tobias Preusser
Persistent Identifier (URN):urn:nbn:de:gbv:579-opus-1002585
Document Type:PhD Thesis
Date of Successful Oral Defense:2015/02/04
Year of Completion:2015
Date of First Publication:2015/02/23
Academic Department:Life Sciences & Chemistry
PhD Degree:Bioinformatics
Focus Area:Health
Library of Congress Classification:R Medicine / RM Therapeutics. Pharmacology / RM300-666 Drugs and their actions / RM345-349 Drugs acting on the cardiovascular system
Call No:Thesis 2015/03

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