Establishment and application of the physiologically-based pharmacokinetic model of amikacin in elderly patients with renal insufficiency

LI Qiaoxi; GUAN Yanping; XIA Chen; WU Lili; WANG Yan

doi:10.6039/j.issn.1001-0408.2023.18.14

您当前的位置：

首页 >

文章列表页 >

Establishment and application of the physiologically-based pharmacokinetic model of amikacin in elderly patients with renal insufficiency

更新时间：2025-09-26

- Establishment and application of the physiologically-based pharmacokinetic model of amikacin in elderly patients with renal insufficiency
- ZHONGGUO YAOFANG Vol. 34, Issue 18, Pages: 2250-2255(2023)
- 作者机构：
  
  1.佛山市第一人民医院药学部，广东佛山　528000
  2.中山大学药学院临床药理研究所，广州　510030
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2023.18.14
  CLC： R969.1
- Received：19 March 2023，
  
  Revised：2023-08-26，
  
  Accepted：28 August 2023，
  
  Published：30 September 2023
- 稿件说明：
移动端阅览
李乔希,管宴萍,夏晨,等.阿米卡星在老年肾功能不全患者中生理药动学模型的建立与应用[J].中国药房,2023,34(18):2250-2255.

LI Qiaoxi,GUAN Yanping,XIA Chen,et al.Establishment and application of the physiologically-based pharmacokinetic model of amikacin in elderly patients with renal insufficiency[J].ZHONGGUO YAOFANG,2023,34(18):2250-2255.
李乔希,管宴萍,夏晨,等.阿米卡星在老年肾功能不全患者中生理药动学模型的建立与应用[J].中国药房,2023,34(18):2250-2255. DOI： 10.6039/j.issn.1001-0408.2023.18.14.

LI Qiaoxi,GUAN Yanping,XIA Chen,et al.Establishment and application of the physiologically-based pharmacokinetic model of amikacin in elderly patients with renal insufficiency[J].ZHONGGUO YAOFANG,2023,34(18):2250-2255. DOI： 10.6039/j.issn.1001-0408.2023.18.14.

摘要

目的

建立阿米卡星在老年肾功能不全患者中的生理药动学（PBPK）模型。

方法

使用PK-SIM

软件进行模型的构建、拟合和模拟。通过查询文献资料，收集阿米卡星的理化性质和体内药动学特性参数，结合软件内置人体模型建立成人PBPK模型并外推至老年PBPK模型。使用临床药动学研究数据对模型进行拟合优化和验证，以拟合优度、相对残差和平均折叠误差为指标评价模型预测性能。使用最终模型模拟老年肾功能不全患者给药后的体内暴露情况，对临床常用给药方案的有效性和安全性进行评估，并给出推荐的给药方案。

结果

建立的阿米卡星PBPK模型在成人和老年患者中均有较好的预测性能，相对残差绝对值均数为25%；各模拟场合下，峰浓度（

max

）和药时曲线下面积（AUC

0－∞

）的平均折叠误差均在＞0.5～＜2范围内。模拟结果显示，与健康成人相比，相同给药方案下老年肾功能不全患者的

max

差异较小，因蓄积引起的谷浓度显著升高。与减少剂量相比，延长阿米卡星给药间隔更有助于保证疗效，减少肾毒性的发生

。

结论

成功建立了阿米卡星在老年肾功能不全患者中的PBPK模型，且模型具有良好的预测性能。

Abstract

OBJECTIVE

To establish a physiologically-based pharmacokinetic （PBPK） model of amikacin in elderly patients with renal insufficiency.

METHODS

PK-SIM

software was adopted for model building， optimization and simulation. The physical and chemical properties and pharmacokinetic parameters related to amikacin were collected by literature review. The PBPK model on adults was established and extrapolated to the elderly population based on the built-in human model. Data from clinical PK studies were used to optimize and validate the model. The goodness of fit， relative residual， and mean folding error （MFE） were used to evaluate the performance of forecasting. The final model was employed to simulate the exposure of amikacin in the elderly population with renal insufficiency， and the efficacy and safety of commonly used clinical dosing regimens were evaluated， and the recommended regimens were proposed.

RESULTS

The established PBPK model of amikacin had good prediction performance in both adult and elderly populations， with the absolute mean of relative residual value of 25%； the MFE of peak concentration （

max

） and area under the plasma concentration curve （AUC

0－∞

） in all simulation occasions ranged ＞0.5-＜2. The simulation results showed that， compared with healthy adults， no significant clinical difference in

max

was observed in the elderly with renal insufficiency at the same dosing regimen， but the trough concentration increased significantly due to accumulation. Prolonging the administration interval of amikacin rather than reducing the dosage was more helpful to ensure the efficacy and to reduce the occurrence of nephrotoxicity.

CONCLUSIONS

The PBPK model for amikacin is successfully established in the elderly patient with renal insufficiency， and shows good predictive performance.

关键词

Keywords

references

KATO H ， HAGIHARA M ， HIRAI J ， et al . Evaluation of amikacin pharmacokinetics and pharmacodynamics for optimal initial dosing regimen [J ] . Drugs R D ， 2017 ， 17 （ 1 ）： 177 - 187 .

KATO H ， PARKER S L ， ROBERTS J A ， et al . Population pharmacokinetics analysis of amikacin initial dosing regimen in elderly patients [J ] . Antibiotics ， 2021 ， 10 （ 2 ）： 100 .

BEAUCAIRE G . Does once-daily dosing prevent nephrotoxicity in all aminoglycosides equally? [J ] . Clin Microbiol Infect ， 2000 ， 6 （ 7 ）： 357 - 362 .

EYLER R F ， MUELLER B A . Antibiotic pharmacokinetic and pharmacodynamic considerations in patients with kidney disease [J ] . Adv Chronic Kidney Dis ， 2010 ， 17 （ 5 ）： 392 - 403 .

SHI S J ， KLOTZ U . Age-related changes in pharmacokinetics [J ] . Curr Drug Metab ， 2011 ， 12 （ 7 ）： 601 - 610 .

焦正，李新刚，尚德为，等 . 模型引导的精准用药：中国专家共识： 2021版 [J ] . 中国临床药理学与治疗学， 2021 ， 26 （ 11 ）： 1215 - 1228 .

LODE H ， GRUNERT K ， KOEPPE P ， et al . Pharmacokinetic and clinical studies with amikacin，a new aminoglycoside antibiotic [J ] . J Infect Dis ， 1976 ，134（SUPPL）：S316- S322 .

GARRAFFO R ， DRUGEON H B ， DELLAMONICA P ， et al . Determination of optimal dosage regimen for amikacin in healthy volunteers by study of pharmacokinetics and bactericidal activity [J ] . Antimicrob Agents Chemother ， 1990 ， 34 （ 4 ）： 614 - 621 .

BARBHAIYA R H ， KNUPP C A ， PFEFFER M ， et al . Lack of pharmacokinetic interaction between cefepime and amikacin in humans [J ] . Antimicrob Agents Chemother ， 1992 ， 36 （ 7 ）： 1382 - 1386 .

BYL B ， BARAN D ， JACOBS F ， et al . Serum pharmacokinetics and sputum penetration of amikacin 30 mg/kg once daily and of ceftazidime 200 mg/kg/day as a continuous infusion in cystic fibrosis patients [J ] . J Antimicrob Chemother ， 2001 ， 48 （ 2 ）： 325 - 327 .

张沂，王洪武，王睿，等 . 阿米卡星的临床药动学与体内抗生素后效应 [J ] . 中国药学杂志， 2000 ， 35 （ 5 ）： 321 - 323 .

阚全程，张晓坚，师秀琴，等 . 健康者体内头孢唑林对阿米卡星药动学的影响 [J ] . 中国抗生素杂志， 2000 ， 25 （ 4 ）： 292 - 293 .

张沂，王洪武，聂舟山，等 . 阿米卡星在不同年龄呼吸系统感染病人中的药物动力学 [J ] . 中国抗生素杂志， 1999 ， 24 （ 4 ）： 297 - 299 .

SULTAN E ， RICHARD C ， PEZZANO M ， et al . Pharmacokinetics of pefloxacin and amikacin administered simultaneously to intensive care patients [J ] . Eur J Clin Pharmacol ， 1988 ， 34 （ 6 ）： 637 - 643 .

VANHAEVERBEEK M ， SISKA G ， HERCHUELZ A . Pharmacokinetics of once-daily amikacin in elderly patients [J ] . J Antimicrob Chemother ， 1993 ， 31 （ 1 ）： 185 - 187 .

PECHERE J C ， DUGAL R . Clinical pharmacokinetics of aminoglycoside antibiotics [J ] . Clin Pharmacokinet ， 1979 ， 4 （ 3 ）： 170 - 199 .

VOGELSTEIN B ， KOWARSKI A ， LIETMAN P S . The pharmacokinetics of amikacin in children [J ] . J Pediatr ， 1977 ， 91 （ 2 ）： 333 - 339 .

KIRBY W M ， CLARKE J T ， LIBKE R D ， et al . Clinical pharmacology of amikacin and kanamycin [J ] . J Infect Dis ， 1976 ，134（SUPPL）：S312- S315 .

PETERS S A ， DOLGOS H . Requirements to establishing confidence in physiologically based pharmacokinetic（PBPK）models and overcoming some of the challenges to meeting them [J ] . Clin Pharmacokinet ， 2019 ， 58 （ 11 ）： 1355 - 1371 .

RADKE C ， HORN D ， LANCKOHR C ， et al . Development of a physiologically based pharmacokinetic modelling approach to predict the pharmacokinetics of vancomycin in critically ill septic patients [J ] . Clin Pharmacokinet ， 2017 ， 56 （ 7 ）： 759 - 779 .

SAGER J E ， YU J J ， RAGUENEAU-MAJLESSI I ， et al . Physiologically based pharmacokinetic（PBPK）modeling and simulation approaches：a systematic review of published models，applications，and model verification [J ] . Drug Metab Dispos ， 2015 ， 43 （ 11 ）： 1823 - 1837 .

FERREIRA A ， MARTINS H ， OLIVEIRA J C ， et al . PBPK modeling and simulation of antibiotics amikacin，gentamicin，tobramycin，and vancomycin used in hospital practice [J ] . Life ， 2021 ， 11 （ 11 ）： 1130 .

BEAUCHAMP D ， LABRECQUE G . Aminoglycoside nephrotoxicity：do time and frequency of administration matter? [J ] . Curr Opin Crit Care ， 2001 ， 7 （ 6 ）： 401 - 408 .

UDY A A ， ROBERTS J A ， LIPMAN J . Clinical implications of antibiotic pharmacokinetic principles in the critically ill [J ] . Intensive Care Med ， 2013 ， 39 （ 12 ）： 2070 - 2082 .

MAHMOUDI L ， MOHAMMADPOUR A H ， AHMADI A ， et al . Influence of sepsis on higher daily dose of amikacin pharmacokinetics in critically ill patients [J ] . Eur Rev Med Pharmacol Sci ， 2013 ， 17 （ 3 ）： 285 - 291 .

FROST K J ， HAMILTON R A ， HUGHES S ， et al . Syste-matic review of high-dose amikacin regimens for the treatment of Gram-negative infections based on EUCAST dosing recommendations [J ] . Eur J Hosp Pharm ， 2023 ， 30 （ 4 ）： 189 - 195 .

刘鑫，付强，杜小莉，等 . 药代动力学/药效动力学在危重症患者抗生素治疗方案优化中的应用及研究进展 [J ] . 中国科学：生命科学， 2021 ， 51 （ 8 ）： 1107 - 1117 .

Views

409

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

肾功能不全痛风患者临床药疗方案的研究进展

肾功能不全合并高血压住院患者经药物摄入钠盐情况的调查

Clinical Observation of Sacubitril Valsartan Sodium Tablets Combined with Bailing Capsules in the Treatment of Chronic Left Heart Failure with Renal Insufficiency

Analysis of Clinical Efficacy of Recombinant Human Brain Natriuretic Peptide Combined with Levosimendan in the Treatment of Acute Decompensated Heart Failure Complicated with Renal Insufficiency

Related Author

吴萍王明丽邹素兰

李泽华万波劳海燕黄志恒

ZHANG Yaling

LI Ming

TAN Gang

LI Xiaoping

HUANG Hui

CHEN Gong

Related Institution

No data

Address：8th Floor, Sihuan Building, No. 129 Daping Main Street, Yuzhong District, Chongqing, China Postal code：400042
Technical support is provided by Beijing Founder Electronics co., LTD 渝ICP备15012710号公网安备50010302001817
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰