title: The Promises of Quantitative Proteomics in Precision Medicine.
abstract: Precision medicine approach has a potential to ensure optimum efficacy and safety of drugs at individual patient level. Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models could play a significant role in precision medicine by predicting interindividual variability in drug disposition and response. In order to develop robust PBPK/PD models, it is imperative that the critical physiological parameters affecting drug disposition and response and their variability are precisely characterized. Currently used PBPK/PD modeling software, for example, Simcyp and Gastroplus, encompass information such as organ volumes, blood flows to organs, body fat composition, glomerular filtration rate, etc. However, the information on the interindividual variability of the majority of the proteins associated with PK and PD, for example, drug metabolizing enzymes, transporters, and receptors, are not fully incorporated into these PBPK modeling platforms. Such information is significant because the population factors such as age, genotype, disease, and gender can affect abundance or activity of these proteins. To fill this critical knowledge gap, mass spectrometry-based quantitative proteomics has emerged as an important technique to characterize interindividual variability in the protein abundance of drug metabolizing enzymes, transporters, and receptors. Integration of these quantitative proteomics data into in silico PBPK/PD modeling tools will be crucial toward precision medicine.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, P.O. Box 357610, Washington 98195. Electronic address: bhagwat@uw.edu.
authors.forename: Bhagwat
authors.initials: B
authors.lastname: Prasad
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, P.O. Box 357610, Washington 98195.
authors.forename: Marc
authors.initials: M
authors.lastname: Vrana
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, P.O. Box 357610, Washington 98195.
authors.forename: Aanchal
authors.initials: A
authors.lastname: Mehrotra
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, P.O. Box 357610, Washington 98195.
authors.forename: Katherine
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, P.O. Box 357610, Washington 98195.
authors.forename: Deepak Kumar
authors.initials: DK
authors.lastname: Bhatt
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000502:physiology; D057285:Precision Medicine / Q000379:methods* / Q000639:trends; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D040901:Proteomics / Q000379:methods* / Q000639:trends; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D004364:Pharmaceutical Preparations
keywords: drug metabolizing enzymes; individualized drug therapy; pharmacokinetic/pharmacodynamic models; physiologically based pharmacokinetic modeling; population pharmacokinetics/pharmacodynamics; proteomics; transporters