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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BioMed Central
2018-09-01
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| Series: | Genomics & Informatics |
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| author | Jaeseong Oh Sojeong Yi Namyi Gu Dongseong Shin Kyung-Sang Yu Seo Hyun Yoon Joo-Youn Cho In-Jin Jang |
| author_facet | Jaeseong Oh Sojeong Yi Namyi Gu Dongseong Shin Kyung-Sang Yu Seo Hyun Yoon Joo-Youn Cho In-Jin Jang |
| author_sort | Jaeseong Oh |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-c9749d02326f4c43a99c73c9afd57778 |
| institution | Kabale University |
| issn | 2234-0742 |
| language | English |
| publishDate | 2018-09-01 |
| publisher | BioMed Central |
| record_format | Article |
| series | Genomics & Informatics |
| spelling | doaj-art-c9749d02326f4c43a99c73c9afd577782025-02-02T17:51:18ZengBioMed CentralGenomics & Informatics2234-07422018-09-01163525810.5808/GI.2018.16.3.52513Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular EntityJaeseong Oh0Sojeong Yi1Namyi Gu2Dongseong Shin3Kyung-Sang Yu4Seo Hyun Yoon5Joo-Youn Cho6In-Jin Jang7 Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 03080, Korea Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 10903, USA Department of Clinical Pharmacology and Therapeutics, Clinical Trial Center, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang 10326, Korea Clinical Trials Center, Gachon University Gil Medical Center, Incheon 21565, Korea Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 03080, Korea Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 03080, Korea Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 03080, Korea Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 03080, KoreaIn 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.http://genominfo.org/upload/pdf/gi-2018-16-3-52.pdfclinical trialmetabolomicsnew drug developmentpharmacogenomics |
| spellingShingle | Jaeseong Oh Sojeong Yi Namyi Gu Dongseong Shin Kyung-Sang Yu Seo Hyun Yoon Joo-Youn Cho In-Jin Jang Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity Genomics & Informatics clinical trial metabolomics new drug development pharmacogenomics |
| 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 | clinical trial metabolomics new drug development pharmacogenomics |
| url | http://genominfo.org/upload/pdf/gi-2018-16-3-52.pdf |
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