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研究生：	蔡孟達 Tsai, Meng-Ta
論文名稱：	藥物計量學於心臟外科患者臨床決策之應用 Application of Pharmacometrics on the Clinical Decision for Cardiac Surgery Patients
指導教授：	周辰熹 Chou, Chen-Hsi
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床藥學與藥物科技研究所 Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年：	2024
畢業學年度：	112
語文別：	英文
論文頁數：	118
中文關鍵詞：	藥物計量學、混合效應模型、心臟外科、萬古黴素
外文關鍵詞：	Pharmacometrics, Mixed effects model, Cardiac surgery, Vancomycin
ORCID：	0000-0003-3893-4645
相關次數：	點閱：58 下載：0
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心臟外科醫師面臨病情危重、情況複雜的多樣性患者。心臟外科中的某些臨床情境可能難以取得足夠且平衡的患者數量或數據，因而無法以傳統的臨床研究來闡明。藥物計量學著重於使用數學模型，特別是混合效應或群體藥物動力學模型來描述臨床觀察到的“劑量-反應-時間”關係，且可以用有意義的臨床因子解釋受試者反應之間的變異性，並允許稀疏和不平衡的數據。本論文的目的是將藥物計量學應用於特定的心臟手術族群，以幫助臨床決策並改善患者預後。
我們開發了兩種穩健的混合效應模型，一種非線性模型用於描述葉克膜和連續性透析對萬古黴素藥物動力學的影響，另一種線性模型用於解釋心臟手術期間在胸骨斷面塗抹萬古黴素後的血中濃度變化。這兩個模型都能夠使用蒙特卡羅模擬對該族群患者提出重要的臨床建議。我們的經驗顯示藥物計量學模型與臨床心臟外科研究的結合可以成為改善臨床成果的重要方法。

Cardiac surgeons face heterogeneous patients in critically ill and complex situations. Some clinical questions in cardiac surgery practice are difficult to clarify with conventional clinical studies because of the limited enrollment of large patient numbers or rich, balanced data. Pharmacometrics describes clinically observed dose-response-time relationships using mathematical models, especially mixed effects or population pharmacokinetic models, which can explain between-subject variability with meaningful clinical factors and
allow sparse and unbalanced data. This dissertation aims to apply pharmacometrics in specific groups of cardiac surgery patients to aid clinical decisions and improve patient prognosis.
We developed two robust mixed effects models, one non-linear to describe the effects of extracorporeal membrane oxygenation and continuous renal replacement therapy on vancomycin pharmacokinetics and one linear to explain the plasma exposure after topical vancomycin over the cut sternal edge during cardiac surgery. Both models can make essential recommendations in the investigated populations using Monte-Carlo simulations. Our experience demonstrated that combining pharmacometrics with clinical cardiac surgery studies can be a valuable approach to improving clinical outcomes.

Certificate of Approval for Doctoral Dissertation I
Abstract II
中文摘要 VI
Acknowledgments X
Table of Contents XI
List of Tables XV
List of Figures XVI
List of Abbreviations XVII
Chapter 1. General Introduction and Outline of the Dissertation 1
1.1. Clinical applications of pharmacometrics 1
1.2. Pharmacometrics in cardiac surgery 2
1.3. Outline of the projects in this dissertation 5
Chapter 2. Non-Linear Mixed Effects Modeling of Vancomycin in Cardiac ICU Patients with Time-Varying Status of Temporary Mechanical Circulatory Support or Continuous Renal Replacement Therapy 7
2.1. Background	7
2.2. Methods 10
2.2.1. Patients and data collection 10
2.2.2. Temporary mechanical circulatory support management 10
2.2.3. PK sampling and vancomycin assay	11
2.2.4. Statistical analysis and pharmacokinetic modeling 11
2.2.5. Model diagnostics and validation 12
2.2.6. Dosing simulation 13
2.3. Results 14
2.3.1. Patient characteristics 14
2.3.2. Population pharmacokinetic modeling 19
2.3.3. Model diagnostics and internal validation 19
2.3.4. External validation 26
2.3.5. Dosing simulation 29
2.4. Discussion 35
2.4.1. Key findings 35
2.4.2. Comparison with previous studies 35
2.4.3. Effect of tMCS on intercompartmental clearance 38
2.4.4. Limitations 39
2.5. Conclusion 40
Chapter 3. Linear Mixed Effects Modeling for Plasma Exposure after Topical Vancomycin over the Cut Sternal Edge during Cardiac Surgery 41
3.1. Background	41
3.2. Methods 42
3.2.1. Patients and data collection 42
3.2.2. Vancomycin assay 42
3.2.3. Statistical analysis and linear mixed effects modeling 43
3.2.4. Model diagnostics 44
3.2.5. Dosing simulations 44
3.3. Results 44
3.3.1. Patient characteristics 44
3.3.2. Linear mixed effects modeling 50
3.3.3. Model diagnostics 52
3.3.4. Dosing simulation 55
3.4. Discussion 58
3.4.1. Key findings 58
3.4.2. Comparison with previous studies 58
3.4.3. Effect of body size and renal function 59
3.4.4. Limitations 60
3.5.	Conclusion 60
Chapter 4. Population Pharmacokinetics for Mycophenolic Acid Exposure in Heart Transplant Patients Receiving Stepwise-Decrease Mycophenolate Mofetil Protocol 61
4.1. Background	61
4.2. Methods 62
4.2.1. Patient and data collection 62
4.2.2. PK sampling and MPA assay 63
4.2.3. Statistical and population PK analysis 63
4.3. Results 64
4.3.1. Patient characteristics 64
4.3.2. Population PK modeling 64
4.4. Discussion 69
4.5. Conclusion 69
Chapter 5. General Conclusion and Future Perspectives 70
References 72
Appendix 79
Appendix 1. IRB approval for the projects in the dissertation. 79
Appendix 2. Vancomycin assay used in previous population PK studies. 82
Appendix 3. Quality of vancomycin HPLC assay. 83
Appendix 4. Modeling process for the vancomycin population PK under tMCS or CRRT model in Chapter 2. 84
Appendix 5. Individual fit of non-compartmental analysis in Chapter 2. 93
Appendix 6. Bootstrap histogram of the final model in Chapter 2. 94
Appendix 7. Selected simulation scenario demonstrating the time-varying effect of with or without tMCS or CRRT. 95
Appendix 8. Patient inclusion and protocol for the topical sternal vancomycin study in Chapter 3. 98
Appendix 9. Modeling process for the plasma exposure after topical sternal vancomycin in Chapter 3. 99
                                    

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