title: Model-Based Individualized Treatment of Chemotherapeutics: Bayesian Population Modeling and Dose Optimization.
abstract: 6-Mercaptopurine (6-MP) is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN) through enzymatic reaction involving thiopurine methyltransferase (TPMT). Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP's widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited. In addition, research efforts devoted on pharmacogenomics to predict clinical responses are proving far from ideal. In this work, we present a Bayesian population modeling approach to develop a pharmacological model for 6-MP metabolism in humans. In the face of scarcity of data in clinical settings, a global sensitivity analysis based model reduction approach is used to minimize the parameter space. For accurate estimation of sensitive parameters, robust optimal experimental design based on D-optimality criteria was exploited. With the patient-specific model, a model predictive control algorithm is used to optimize the dose scheduling with the objective of maintaining the 6-TGN concentration within its therapeutic window. More importantly, for the first time, we show how the incorporation of information from different levels of biological chain-of response (i.e. gene expression-enzyme phenotype-drug phenotype) plays a critical role in determining the uncertainty in predicting therapeutic target. The model and the control approach can be utilized in the clinical setting to individualize 6-MP dosing based on the patient's ability to metabolize the drug instead of the traditional standard-dose-for-all approach.
authors.affiliation: School of Chemical Engineering, Purdue University, 480 Stadium Mall Way, West Lafayette, IN, 47907, United States of America.
authors.forename: Devaraj
authors.initials: D
authors.lastname: Jayachandran
authors.affiliation: School of Chemical Engineering, Purdue University, 480 Stadium Mall Way, West Lafayette, IN, 47907, United States of America.
authors.forename: José
authors.initials: J
authors.lastname: Laínez-Aguirre
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, 206 South Martin Jischke Drive, West Lafayette, IN, 47907, United States of America.
authors.forename: Ann
authors.initials: A
authors.lastname: Rundell
authors.affiliation: Riley Hospital for Children, 702 Barnhill Drive, Indianapolis, IN, 46202, United States of America.
authors.forename: Terry
authors.initials: T
authors.lastname: Vik
authors.affiliation: School of Chemical Engineering, Purdue University, 480 Stadium Mall Way, West Lafayette, IN, 47907, United States of America; Weldon School of Biomedical Engineering, Purdue University, 206 South Martin Jischke Drive, West Lafayette, IN, 47907, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Hannemann
authors.affiliation: School of Chemical Engineering, Purdue University, 480 Stadium Mall Way, West Lafayette, IN, 47907, United States of America.
authors.forename: Gintaras
authors.initials: G
authors.lastname: Reklaitis
authors.affiliation: School of Chemical Engineering, Purdue University, 480 Stadium Mall Way, West Lafayette, IN, 47907, United States of America.
authors.forename: Doraiswami
authors.initials: D
authors.lastname: Ramkrishna
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism; D001499:Bayes Theorem; D056726:Genetic Association Studies; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D057285:Precision Medicine; D011355:Prodrugs / Q000008:administration & dosage* / Q000378:metabolism*; D013873:Thionucleotides / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D011355:Prodrugs; D013873:Thionucleotides; C003964:6-thioguanylic acid; D015122:Mercaptopurine