Title Page
Contents
Abbreviations 13
국문초록 16
ABSTRACT 19
1. Introduction 22
1.1. Tuberculosis: General aspects 22
1.2. Tuberculosis control in the Republic of Korea 25
1.3. Pharmacokinetics of Ethambutol in adult TB patients 27
1.4. Factors associated with Pharmacokinetics of Ethambutol 29
1.5. Therapeutic Drug Monitoring and Population PK model 30
2. Objectives 33
3. Materials and methods 34
3.1. Study protocol 34
3.2. Study population 34
3.2.1. Inclusion criteria 34
3.2.2. Exclusion criteria 34
3.2.3. Diagnosis, treatment and follow-up 35
3.2.4. Patient information 35
3.3. Blood sampling 36
3.4. Determination of EMB plasma concentration 36
3.4.1. Chemicals 36
3.4.2. Preparation of standards and quality control samples 37
3.4.3. Sample preparation 37
3.4.4. EMB plasma concentration analysis 38
3.4.5. Linearity and lower limit of quantification 39
3.4.6. Accuracy and precision 40
3.5. OCT2 genotyping 41
3.5.1. Materials and instruments 41
3.5.2. Buffer preparation 44
3.5.3. Amplification of SLC22A2 fragments 45
3.5.4. Purification of PCR products using ExoSAP-IT 46
3.5.5. SNaPshot reactions 47
3.5.6. SAP reactions 48
3.5.7. SNaPshot analysis 49
3.6. Pharmacokinetics modeling 50
3.6.1. Basic population model selection 51
3.6.2. Covariate selection 52
3.6.3. Model evaluation 53
3.6.4. PK/PD indices calculations 54
4. Results 56
4.1. Characteristics of TB population 56
4.2. Population PK modeling 58
4.2.1. Basic model development, disposition phase 58
4.2.2. Basic model development, absorption phase 61
4.2.3. Basic model development, residual variability 65
4.2.4. Univariate analysis 71
4.2.5. Stepwise evaluation 73
4.2.6. Structure of final model 75
4.2.7. Model evaluation 80
4.2.8. Bayesian estimation of EMB PK parameters 82
4.2.1. PK/PD indices calculations 83
5. Discussion 96
6. Conclusion 104
References 105
Table 1. Global TB target for SDGs, End TB Strategy and political declaration of the UN high-level meeting on TB to 2030 24
Table 2. Primers for SLC22A2 amplification 43
Table 3. Primers for SNaPshot of 3 SNPs of SCL22A2 43
Table 4. Components for amplification of SLC22A2 fragments 45
Table 5. Components of SNaPshot reaction 47
Table 6. Components of SNaPshot analysis 49
Table 7. Blood samples and baseline characteristics of patients in the study 56
Table 8. Comparison of OFV value, minimization process and estimated PK parameters between models of disposition phase 59
Table 9. Comparison of OFV value, minimization process and estimated PK parameters among models of absorption phase 62
Table 10. Comparison of OFV value, minimization process and estimated PK parameters among additive error, proportional error and the combination of additive and proportional error 66
Table 11. Estimated parameters of basic model of EMB 70
Table 12. Summary of univariate analysis 72
Table 13. Summary of step wise evaluation 74
Table 14. EMB population PK parameter estimates for the final model and bootstrap results 75
Table 15. Prediction errors estimated for test set with the final model and published models 81
Table 16. Pharmacokinetic/pharmacodynamic indexes calculations of T>MIC and AUC/MIC for EMB among different renal function groups. 87
Figure 1. "Global TB incidence, 2019" by World Development Indicators, Global Tuberculosis Report - World Health Organization, CC BY 4.0 23
Figure 2. Workflow to develop EMB population PK model 51
Figure 3. Ethambutol plasma concentrations versus time since the last oral dose administration 58
Figure 4. GOF plots of one-compartment (4A) and two-compartment (4B) model. (A) Observed versus population predicted concentrations. (B) Observed versus individual predicted concentrations. (C) Concentration weighted versus population predicted... 60
Figure 5. GOF plots of first-order absorption (5A), first-order absorption with lag time (5B), first-order absorption and zero- order absorption (5C), first-order and transit compartment (5D). (A) Observed versus population predicted concentrations. (B)... 64
Figure 6. GOF plots of additive error (6A), proportional error (6B) and combination of additive and proportional error (6C). (A) Observed versus population predicted concentrations. (B) Observed versus individual predicted concentrations. (C)... 68
Figure 7. GOF plots of basic model of EMB. (A) Observed versus population predicted concentrations. (B) Observed versus individual predicted concentrations.... 71
Figure 8. GOF plots of the final population PK model of EMB. (A) Observed versus population predicted concentration. (B) Observed versus individual predicted... 78
Figure 9. Prediction-corrected visual predictive check of the final model for EMB concentrations. The observed EMB concentrations are shown as black dots. The... 79
Figure 10. Box and whisker plots for prediction performance evaluation, using population prediction and individual prediction in the external validation in our... 82
Figure 11. Relationship between renal function with EMB PK. A) Estimated area under the concentration-time curve from 0 to 24 hours (AUC₀-₂₄h) normalized with... 84
Figure 12. Pharmacokinetics/pharmacodynamics (PK/PD) indices of EMB among renal function groups. Simulations were carried out based on body weight and renal... 85
Figure 13. Probability of achieving a Cmax of≥6 for the simulated EMB dosing regimen according to the renal function groups.[이미지참조] 86
Figure 14. Box plots representing EMB T>MIC among renal function groups based on all MIC values. Simulations were carried out based on body weight and renal... 91
Figure 15. Box plots representing EMB AUC/MIC among renal function groups based on all MIC values. Simulations were carried out based on body weight and... 92
Figure 16. Probability of achieving area under the concentration-versus-time curve to minimal inhibitory concentration of≥119 for the simulated EMB dosing regimens... 94