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Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determi...

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Autores principales: Oh, Jaeseong, Yi, Sojeong, Gu, Namyi, Shin, Dongseong, Yu, Kyung-Sang, Yoon, Seo Hyun, Cho, Joo-Youn, Jang, In-Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society of Gastrointestinal Intervention 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187817/
https://www.ncbi.nlm.nih.gov/pubmed/30309203
http://dx.doi.org/10.5808/GI.2018.16.3.52
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author Oh, Jaeseong
Yi, Sojeong
Gu, Namyi
Shin, Dongseong
Yu, Kyung-Sang
Yoon, Seo Hyun
Cho, Joo-Youn
Jang, In-Jin
author_facet Oh, Jaeseong
Yi, Sojeong
Gu, Namyi
Shin, Dongseong
Yu, Kyung-Sang
Yoon, Seo Hyun
Cho, Joo-Youn
Jang, In-Jin
author_sort Oh, Jaeseong
collection PubMed
description In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.
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spelling pubmed-61878172018-10-17 Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity Oh, Jaeseong Yi, Sojeong Gu, Namyi Shin, Dongseong Yu, Kyung-Sang Yoon, Seo Hyun Cho, Joo-Youn Jang, In-Jin Genomics Inform Original Article In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials. Society of Gastrointestinal Intervention 2018-09 2018-09-30 /pmc/articles/PMC6187817/ /pubmed/30309203 http://dx.doi.org/10.5808/GI.2018.16.3.52 Text en Copyright © 2018 by the Korea Genome Organization It is identical to the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/).
spellingShingle Original Article
Oh, Jaeseong
Yi, Sojeong
Gu, Namyi
Shin, Dongseong
Yu, Kyung-Sang
Yoon, Seo Hyun
Cho, Joo-Youn
Jang, In-Jin
Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity
title Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity
title_full Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity
title_fullStr Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity
title_full_unstemmed Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity
title_short Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity
title_sort utility of integrated analysis of pharmacogenomics and pharmacometabolomics in early phase clinical trial: a case study of a new molecular entity
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187817/
https://www.ncbi.nlm.nih.gov/pubmed/30309203
http://dx.doi.org/10.5808/GI.2018.16.3.52
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