A Personalized Multiscale Modeling Framework for Dose Selection in Precision Medicine

Precision medicine (PM) refers to the use of available genomic information from an individual patient to select the most appropriate therapy for a disease. In this paper, we have developed a mechanistic multiscale modeling framework for the whole human body integrated with human hepatocyte genomic d...

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Published inIndustrial & engineering chemistry research Vol. 59; no. 21; pp. 9819 - 9829
Main Authors Toroghi, Masood Khaksar, Cluett, William R, Mahadevan, Radhakrishnan
Format Journal Article
LanguageEnglish
Published American Chemical Society 27.05.2020
Subjects
adults
amino acids
biomarkers
chemistry
computer simulation
disease progression
drugs
genomics
humans
hyperuricemia
patients
pharmacology
precision medicine
process design
Online AccessGet full text
ISSN0888-5885
1520-5045
1520-5045
DOI10.1021/acs.iecr.0c01070

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Abstract Precision medicine (PM) refers to the use of available genomic information from an individual patient to select the most appropriate therapy for a disease. In this paper, we have developed a mechanistic multiscale modeling framework for the whole human body integrated with human hepatocyte genomic data. The model is validated by estimating the concentrations of several biomarkers in different amino acid inborn errors of metabolism (IEMs). To demonstrate the potential application of our multiscale modeling framework to precision medicine, we present a computational study of a specific disease. In this study, a genetic deficiency called Kelley–Seegmiller syndrome (KSS) is simulated for eight adult patients. Using our approach, we estimate the proper dosage of the drug for each subject needed to prevent hyperuricemia. These in silico results demonstrate that there is a significant difference in the optimal dose of the drug among individuals. In addition, the required dosages for the second and third days are different from those for the first day of treatment in each patient. Both results have important implications in terms of drug efficacy, drug side effects, and cost of the treatment. We also compare the pharmacological effect of available commercial drug tablets with these optimal values on disease progression. The results in this paper highlight the potential of the proposed modeling framework in opening up new opportunities in systems pharmacology and personalized medicine.
AbstractList Precision medicine (PM) refers to the use of available genomic information from an individual patient to select the most appropriate therapy for a disease. In this paper, we have developed a mechanistic multiscale modeling framework for the whole human body integrated with human hepatocyte genomic data. The model is validated by estimating the concentrations of several biomarkers in different amino acid inborn errors of metabolism (IEMs). To demonstrate the potential application of our multiscale modeling framework to precision medicine, we present a computational study of a specific disease. In this study, a genetic deficiency called Kelley–Seegmiller syndrome (KSS) is simulated for eight adult patients. Using our approach, we estimate the proper dosage of the drug for each subject needed to prevent hyperuricemia. These in silico results demonstrate that there is a significant difference in the optimal dose of the drug among individuals. In addition, the required dosages for the second and third days are different from those for the first day of treatment in each patient. Both results have important implications in terms of drug efficacy, drug side effects, and cost of the treatment. We also compare the pharmacological effect of available commercial drug tablets with these optimal values on disease progression. The results in this paper highlight the potential of the proposed modeling framework in opening up new opportunities in systems pharmacology and personalized medicine.
Author Cluett, William R
Toroghi, Masood Khaksar
Mahadevan, Radhakrishnan
AuthorAffiliation Institute of Biomaterials and Biomedical Engineering
Department of Chemical Engineering and Applied Chemistry
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  surname: Mahadevan
  fullname: Mahadevan, Radhakrishnan
  email: krishna.mahadevan@utoronto.ca
  organization: Institute of Biomaterials and Biomedical Engineering
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Snippet Precision medicine (PM) refers to the use of available genomic information from an individual patient to select the most appropriate therapy for a disease. In...
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SubjectTerms adults
amino acids
biomarkers
chemistry
computer simulation
disease progression
drugs
genomics
humans
hyperuricemia
patients
pharmacology
precision medicine
process design
Title A Personalized Multiscale Modeling Framework for Dose Selection in Precision Medicine
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