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Personalized drug dosing through modeling and feedback

Author(s):

A. Caruso
Conference/Journal:

no. ETH Diss. 18819, pp. 262
Abstract:

The research work presented in this thesis discusses innovative strategies for the delivery of personalized pharmacologic therapy through modeling and feedback control. The objective is to enable medical practitioners to deliver drug therapies with a higher standard of care, better outcomes and improved patient well being. Individualizing dosing to the specific needs of each patient allows to adequately fulfill the therapeutic requirements of the individual and prevent the risks and inefficacy associated with over- and under-dosing.

In Chapter 1, the topic of personalized drug dosing is introduced in relation to two clinical problems that are addressed in this thesis: the delivery of sedation and the administration of antiplatelet therapy. Also, the structure of this document is outlined.

Chapter 2 discusses the terminology and basic pharmacology concepts that are extensively used throughout the thesis. The goal is to acquaint the reader with the phenomena involved with drug disposition and action on the human body and the mathematical models that have been proposed to describe them.

In Chapter 3, the problem of anesthetic dosing for the delivery of sedation and analgesia is addressed. The pronounced interindividual variability in drug sensitivity and the changing surgical stimulus require to continuously evaluate the pharmacologic effects and personalize anesthetic delivery. Titration to effect is used in the clinical practice to optimize the desired effects (analgesia, sedation and anxiolisys) and minimize the extent of the adverse effects (cardiorespiratory depression). In this thesis, a novel dosing paradigm for the safe and effective delivery of personalized sedation is proposed. A respiratory model is used as a patient simulator for the design of the feedback control dosing strategy and to test the feasibility of the proposed anesthetic paradigm.

Chapter 4 is focused on antiplatelet therapy and the modeling of anticoagulant effects. Optimal platelet inhibition is based on maximizing antithrombotic properties while minimizing bleeding risk, and it is critically dependent on the assessment of the individual sensitivity to the drugs. The objective of the work is to provide a quantitative description of anticoagulant effects and to formulate dosing recommendations in the individual. The study also yields experimental validation for a novel model of pharmacodynamic interactions that combines therapeutic and adverse effects into a comprehensive framework for analysis of drug usefulness.

The main achievements of the research work discussed in this thesis are summarized in Chapter 5, as well as the potential areas for improvement and further investigation.

In Appendices A, B, and C three clinical study protocols addressing further instances of therapy individualization are included. These clinical trials have been planned, prepared, and initiated, however final results are regrettably not available at the time of writing. The aim is to provide the reader with a more comprehensive insight into the range of projects directed at personalizing drug delivery that were undertaken within the scope of the PhD work.

Year:

2009
Type of Publication:

(03)Ph.D. Thesis
Supervisor:

M. Morari

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% Autogenerated BibTeX entry
@PhDThesis { Xxx:2009:IFA_3502,
    author={A. Caruso},
    title={{Personalized drug dosing through modeling and feedback}},
    school={},
    year={2009},
    address={},
    month=dec,
    url={http://control.ee.ethz.ch/index.cgi?page=publications;action=details;id=3502}
}
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