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Population pharmacokinetic analysis of GX-E2, a novel erythropoiesis stimulating agent, in healthy male subjects : 새로운 적혈구 생성 촉진제인 GX-E2의 집단 약동학 분석
DC Field | Value | Language |
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dc.contributor.advisor | 유경상 | - |
dc.contributor.author | 윤수민 | - |
dc.date.accessioned | 2018-05-29T04:51:24Z | - |
dc.date.available | 2018-05-29T04:51:24Z | - |
dc.date.issued | 2018-02 | - |
dc.identifier.other | 000000149669 | - |
dc.identifier.uri | https://hdl.handle.net/10371/142300 | - |
dc.description | 학위논문 (석사)-- 서울대학교 대학원 : 의과대학 의과학과, 2018. 2. 유경상. | - |
dc.description.abstract | Introduction: GX-E2 is a novel erythropoiesis stimulating agent which is human erythropoietin (EPO) fused with Fc region of the antibody. The pharmacokinetic (PK)/pharmacodynamic (PD) properties following a single intravenous (IV) and subcutaneous (SC) injection of GX-E2 have been revealed by the noncompartmental analysis of preclinical and clinical study. The SC injection of GX-E2 presented the extended mean residence time and duration of action than currently marketed EPO. The objective of this study was to characterize the PK properties following a sin-gle IV and SC injection of GX-E2 by developing population PK models.
Methods: For the model development, data were pooled from two phase I clinical trials. Two different approaches were applied for describing the disposition of GX-E2: Simple disposition model in which describes the model with Michaelis-Menten enzyme kinetics were tested. Target-mediated drug disposition (TMDD) model was tested for mechanistic understanding of PK properties. Each model was numerically and graphically diagnosed to select the final model. Visual predictive check was per-formed to validate the predictive performance of the final model. Results: A total of 1084 serum GX-E2 concentrations were obtained from 72 sub-jects. The PK properties of GX-E2 were well described by the 2-compartment model with first-order absorption. Both Michaelis-Menten enzyme kinetic model and TMDD model could adequately explain the characteristic PK profiles of GX-E2. An acceptable predictive performance of each final model was validated by the visual predictive check. Approximately 50 – 70% of the SC injected dose was predicted to be absorbed into the systemic circulation with the first-order absorption constant of 0.003 h-1. From the estimated clearances of free-form and bound form, majority of injected GX-E2 are predicted to be eliminated as a bound form. Conclusion: This study first described the PK of GX-E2 by developing population PK models. Both simple disposition model and TMDD model were fitted well with the observed data, how-ever, TMDD model had advantage in reflecting mechanistic aspects of drug. Further assessments of absorption mechanism and inclusion of PD factors in current model will enable to assess the further in-depth understanding of GX-E2 PK profile. | - |
dc.description.tableofcontents | INTRODUCTION 1
METHODS 5 Studies and subjects 5 Bioanalytical methods 8 Population pharmacokinetic analysis 9 Parameter estimation method 9 Simple disposition model 9 Target-mediated drug disposition model 11 Model selection 15 Covariate selection 17 Model validation 18 RESULTS 19 Study populations 19 Exploratory data analysis 21 Population pharmacokinetic analysis 23 Simple disposition model 23 Target-mediated disposition model 32 Model validation 40 DISCUSSION 43 ACKNOWLEDMENTS 47 REFERENCES 48 APPENDICES 51 국문 초록 56 | - |
dc.format | application/pdf | - |
dc.format.extent | 2592509 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Population pharmacokinetics | - |
dc.subject | Michaelis-Menten | - |
dc.subject | target-mediated drug disposition | - |
dc.subject | NONMEM | - |
dc.subject | GX-E2 | - |
dc.subject | erythropoietin stimulating agent | - |
dc.subject.ddc | 610.72 | - |
dc.title | Population pharmacokinetic analysis of GX-E2, a novel erythropoiesis stimulating agent, in healthy male subjects | - |
dc.title.alternative | 새로운 적혈구 생성 촉진제인 GX-E2의 집단 약동학 분석 | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | Yoon, Sumin | - |
dc.description.degree | Master | - |
dc.contributor.affiliation | 의과대학 의과학과 | - |
dc.date.awarded | 2018-02 | - |
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