林慧玲黃金鼎臺灣大學：賴俐君Lai, Lily Li-ChunLily Li-ChunLai2007-11-272018-07-092007-11-272018-07-092004http://ntur.lib.ntu.edu.tw//handle/246246/55433在胺基配醣體類抗生素 (aminoglycoside antibiotics) 的使用上，延長給藥間隔能夠提高治療效果同時降低毒性發生率﹔其設計基礎是建立於胺基配醣體類抗生素的三種特性﹕殺菌效果的濃度依賴性 (concentration-dependent bactericidal activity)、抗生素後效應 (post-antibiotic effect)、以及適應性抗藥性 (adaptive resistance)。 本研究採用回朔性方法，目的在於為臺大醫院的病人群設計關於使用胺基配醣體類抗生素的一套延長給藥間隔的給藥方式。劑量是由血中峰濃度 (gentamicin 16-20 mg/L﹔amikacin 32-40 mg/L) 達到最小抑菌濃度 (minimum inhibitory concentration﹔MIC) 的8-10倍的目標值來決定。給藥間隔則是取決於8個小時的抗生素後效應，以及至少4個小時的藥物淨空期 (drug-free period)。 本研究共納入205筆資料 (gentamicin 110筆﹔amikacin 95筆) 進行分析。利用此群病人之藥品動態學參數來模擬藥物血中濃度的變化曲線，得知，gentamicin 7 mg/kg﹔amikacin 14 mg/kg的劑量能夠在各個不同腎弁鄋滲f人群中，達到目標峰值濃度﹔不過，對於使用24小時的給藥間隔，則只有在腎弁鉊Extended-interval aminoglycoside (EIA) regimens, holding a number of properties, namely concentration-dependent bactericidal activity, post-antibiotic effect (PAE) and adaptive resistance, have been instituted to maximize therapeutic effects and to minimize the potential for toxicity. The purpose of this retrospective study was to design an EIA regimen for gentamicin and amikacin based on the three properties mentioned above. This regimen aimed to comprise of a dose that achieves a serum peak concentration:minimum inhibitory concentration (peak concentration:MIC) ratio of 8:1 to 10:1 (target serum peak concentration of 16 to 20 mg/L for gentamicin and 32 to 40 mg/L for amikacin), and a dosing interval that achieves a balance between an 8-hour PAE period and a sufficient drug-free period of at least 4 hours. A total of 205 datasets (110 in the gentamicin group and 95 in the amikacin group) were included in the analysis of this study. Individual pharmacokinetic profiles were determined, and population pharmacokinetic models were then developed. A 7-mg/kg dose of gentamicin and a 14-mg/kg dose of amikacin were required to achieve the target serum peak concentrations for patients with various degrees of renal function. However, only patients with creatinine clearance ≧70 mL/min for gentamicin and patients with creatinine clearance ≧60 mL/min for amikacin were able to obtain a sufficient drug-free period, not too long beyond the period covered by PAE, with a 24-hour dosing interval. Patients with creatinine clearance values below the cut-off points were therefore suggested to be maintained on the conventional dosing regimen as these individuals likely would not benefit from an EIA regimen. Nonetheless, the appropriateness of the EIA regimen postulated in this study still waits for further clinical validation.Contents page………………………………………………………………………..i Abstract………………………………………………………………………………iv Chapter One Background……………………………………………………..1 Section 1.1 Pharmacokinetics………………………………………………2 1.1.1 Absorption…………………………………………………………2 1.1.2 Distribution………………………………………………………...2 1.1.3 Elimination………………………………………………………...3 1.1.4 Pharmacokinetic model………………………………………….3 Section 1.2 Efficacy…………………………………………………………..5 1.2.1 Concentration-dependent bactericidal activity………………...5 1.2.2 Post-antibiotic effect……………………………………………...6 1.2.3 Adaptive resistance………………………………………………7 Section 1.3 Toxicity…………………………………………………………..9 1.3.1 Nephrotoxicity………………………………………………….....9 1.3.2 Ototoxicity………………………………………………………..10 Section 1.4 Clinical practice………………………………………………..11 1.4.1 Clinical trials……………………………………………………..11 1.4.2 Patient populations……………………………………………..12 1.4.3 Selection of dosing regimens………………………………….12 Chapter Two Study purpose…………………………………………………20 Chapter Three Materials and methods……………………………………….21 Section 3.1 Study design…………………………………………………..21 Section 3.2 Study subjects…………………………………………………22 3.2.1 Inclusion criteria…………………………………………………22 3.2.2 Exclusion criteria………………………………………………..22 Section 3.3 Data collection…………………………………………………24 3.3.1 Study period……………………………………………………..24 3.3.2 Data source……………………………………………………...24 3.3.3 Data contents……………………………………………………24 Section 3.4 Terms and equations………………………………………….26 3.4.1 Targeting MIC……………………………………………………26 3.4.2 Dosing interval based on PAE period…………………………26 3.4.3 Dosing interval based on drug-free period……………………26 3.4.4 Creatinine clearance estimation……………………………….27 3.4.4.1 Normal patients………………………………………….27 3.4.4.2 Patients with unstable renal function………………….28 3.4.4.3 Obese patients…………………………………………..30 3.4.5 Individual pharmacokinetic profile…………………………….31 3.4.6 Serum aminoglycoside concentrations……………………….31 Section 3.5 Data analysis…………………………………………………..32 3.5.1 NTUH patients’ pharmacokinetic profile determination……..32 3.5.1.1 Individual pharmacokinetic profile……………………..32 3.5.1.2 Regression and correlation……………………………..33 3.5.2 Pharmacokinetic model development and EIA regimen determination…………………………………………………….33 3.5.2.1 Pharmacokinetic models………………………………..33 3.5.2.2 Serum aminoglycoside concentrations………………..33 3.5.2.3 EIA regimen………………………………………………33 Chapter Four Results…………………………………………………………35 Section 4.1 NTUH patient data…………………………………………….35 Section 4.2 NTUH patients’ pharmacokinetic profile determination……39 4.2.1 Volume of distribution…………………………………………..39 4.2.2 Elimination rate constant and half-life…………………………39 Section 4.3 Pharmacokinetic model development and EIA regimen determination………………………………………………….44 Section 4.4 Monitoring……………………………………………………...53 Chapter Five Discussion……………………………………………………..55 Section 5.1 EIA regimen……………………………………………………55 5.1.1 Dose……………………………………………………………...55 5.1.2 Dosing interval…………………………………………………..56 Section 5.2 Possible variations……………………………………………59 Section 5.3 Current EIA prescribing habit………………………………..61 Section 5.4 Limitations……………………………………………………..62 Chapter Six Conclusion…………………………………………………….63 Appendix I…………………………………………………………………………..64 Section A1.1 Theoretical pharmacokinetic model simulation…………….64 Appendix II………………………………………………………………………….68 Section A2.1 Creatinine clearance estimation……………………………..68 A2.1.1 Normal patients………………………………………………….68 A2.1.2 Patients with unstable renal function………………………….73 A2.1.3 Obese patients…………………………………………………..82 Appendix III…………………………………………………………………………93 Section A3.1 Pharmacokinetic model simulation.…………………………93 Appendix IV…………………………………………………………………………97 Section A4.1 Current EIA prescribing habit………………………………...97 Reference………………………………………………………………………...1012472236 bytesapplication/pdfen-US藥品動態學參數延長給藥間隔藥物血中濃度變化曲線胺基配醣體類抗生素EIAindividual pharmacokinetic profilesextended-interval aminoglycosidepopulation pharmacokinetic modelstexthttp://ntur.lib.ntu.edu.tw/bitstream/246246/55433/1/ntu-93-R91451014-1.pdf