• 제목/요약/키워드: Clinical pharmacology

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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

  • Oh, Jaeseong;Yi, Sojeong;Gu, Namyi;Shin, Dongseong;Yu, Kyung-Sang;Yoon, Seo Hyun;Cho, Joo-Youn;Jang, In-Jin
    • Genomics & Informatics
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    • 제16권3호
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    • pp.52-58
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    • 2018

  • 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.

  • https://doi.org/10.5808/GI.2018.16.3.52 인용 PDF KSCI

db/db 마우스에서 상엽, 귀전우, 인삼 복합처방의 항당뇨 활성 (Antidiabetic Effect of Herbal Formula Containing Mori Folium, Euonymi Lignum Suberalatum and Ginseng Radix in db/db Mice)

  • 박금주;한은정;최윤숙;한기철;박종석;정성현
    • 생약학회지
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    • 제38권1호
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    • pp.10-14
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    • 2007

  • Type 2 diabetes mellitus relavant to insulin resistance is a chronic and hard to control. In order to develop an antidiabetic agent from natural products, anti-hyperglycemic effect of herbal formula containing Mori Follium, Euonymi Lignum Suberalatum and Ginseng Radix(MEG) was investigated in db/db mice. Treatment group was administered orally with MEG formula at a dose of 300 mg/kg for 5 weeks, and blood glucose, insulin and lipid levels were determined. MEG treatment group showed a marked decrease in fasting blood glucose level and insulin resistance index(IRI) compared to those in diabetic control. Improvement of insulin resistance(60.6%) was indicative of reducing lipid levels in plasma and triglyceride contents in muscle and adipose tissue. In addition, expressions of an insulin responsive gene, glucose transporter 4(Glut4), in muscle and adipose tissue were upregulated in MEG treatment group. Compared islet morphology between groups, MEG formula prevented the ${\beta}$-cell destruction caused by high blood glucose. Taken together, MEG formula can act as an anti-hyperglycemic agent with insulin sensitizing effect, and thus deserves a clinical trial in the future.

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Clinical Geriatric Pharmacology

  • Sohn, Dong-Ryul
    • 한국응용약물학회:학술대회논문집
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    • 한국응용약물학회 1997년도 추계학술대회
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    • pp.87-91
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    • 1997

  • The range of disorders of old age that are thought potentially amenable to drug therapy is increasing. However, factors such as the growing costs of drug development and prescription, the novel pharmacological profile and enhanced potency of many new compounds, and the concerns that the elderly may have enhanced susceptibility to toxicity all make drug usage in the elderly patient an increasingly specialized topic. This is compounded by the high incidence of multiple disorders in frail elderly patients, and consequently the possibility of the long term use of several drugs, thus, adding the risk of drug interactions. Thus, clinical pharmacology in the elderly requires understanding of pharmacologic characteristic determinants of the physiological changes (Table 1) associated with aging in terms of pharmacokinetics and pharmacodynamics.

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Prediction of the human in vivo antiplatelet effect of S- and R-indobufen using population pharmacodynamic modeling and simulation based on in vitro platelet aggregation test

  • Noh, Yook-Hwan;Han, Sungpil;Choe, Sangmin;Jung, Jin-Ah;Jung, Jin-Ah;Hwang, Ae-Kyung;Lim, Hyeong-Seok
    • Translational and Clinical Pharmacology
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    • 제26권4호
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    • pp.160-165
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    • 2018

  • Indobufen ($Ibustrin^{(R)}$), a reversible inhibitor of platelet aggregation, exists in two enantiomeric forms in 1:1 ratio. Here, we characterized the anti-platelet effect of S- and R-indobufen using response surface modeling using $NONMEM^{(R)}$ and predicted the therapeutic doses exerting the maximal efficacy of each enantioselective S- and R-indobufen formulation. S- and R-indobufen were added individually or together to 24 plasma samples from drug-naïve healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0-128 mg/L. Collagen-induced platelet aggregation in platelet-rich plasma was determined using a Chrono-log Lumi-Aggregometer. Inhibitory sigmoid $I_{max}$ model adequately described the anti-platelet effect. The S-form was more potent, whereas the R-form showed less inter-individual variation. No significant interaction was observed between the two enantiomers. The anti-platelet effect of multiple treatments with 200 mg indobufen twice daily doses was predicted in the simulation study, and the effect of S- or R-indobufen alone at various doses was predicted to define optimal dosing regimen for each enantiomer. Simulation study predicted that 200 mg twice daily administration of S-indobufen alone will produce more treatment effect than S-and R-mixture formulation. S-indobufen produced treatment effect at lower concentration than R-indobufen. However, inter-individual variation of the pharmacodynamic response was smaller in R-indobufen. The present study suggests the optimal doses of R-and S-enantioselective indobufen formulations in terms of treatment efficacy for patients with thromboembolic problems. The proposed methodology in this study can be applied to the develop novel enantio-selective drugs more efficiently.

  • https://doi.org/10.12793/tcp.2018.26.4.160 인용