V. Gotta, J. Bielicki, P. Paioni, Chantal Csajka, Dominic Stefan Bräm, Christoph Berger, Elisabeth Giger, Michael Buettcher, K. Posfay-Barbe, J. van den Anker, Marc Pfister
{"title":"用于促进新生儿科国家剂量标准化进程的药物计量学硅学研究--应用于阿米卡星。","authors":"V. Gotta, J. Bielicki, P. Paioni, Chantal Csajka, Dominic Stefan Bräm, Christoph Berger, Elisabeth Giger, Michael Buettcher, K. Posfay-Barbe, J. van den Anker, Marc Pfister","doi":"10.57187/s.3632","DOIUrl":null,"url":null,"abstract":"BACKGROUND AND AIMS\nPharmacometric in silico approaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study.\n\n\nMETHODS\nAmikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30-35 weeks and a post-natal age of 0-14 days (\"subpopulation of clinical concern\"), as potentially oto-/nephrotoxic trough concentrations (Ctrough >5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough (Ctrough <5 mg/l) dosages in most neonates.\n\n\nRESULTS\nIn the subpopulation of clinical concern, Ctrough <5 mg/l was predicted in 59% versus 79-99% of cases in all other subpopulations following the current recommendations. Elevated Ctrough values were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctrough below 5 mg/l to >80%.\n\n\nCONCLUSION\nPharmacometric in silico studies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.","PeriodicalId":22111,"journal":{"name":"Swiss medical weekly","volume":null,"pages":null},"PeriodicalIF":2.1000,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology - application to amikacin.\",\"authors\":\"V. Gotta, J. Bielicki, P. Paioni, Chantal Csajka, Dominic Stefan Bräm, Christoph Berger, Elisabeth Giger, Michael Buettcher, K. Posfay-Barbe, J. van den Anker, Marc Pfister\",\"doi\":\"10.57187/s.3632\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"BACKGROUND AND AIMS\\nPharmacometric in silico approaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study.\\n\\n\\nMETHODS\\nAmikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30-35 weeks and a post-natal age of 0-14 days (\\\"subpopulation of clinical concern\\\"), as potentially oto-/nephrotoxic trough concentrations (Ctrough >5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough (Ctrough <5 mg/l) dosages in most neonates.\\n\\n\\nRESULTS\\nIn the subpopulation of clinical concern, Ctrough <5 mg/l was predicted in 59% versus 79-99% of cases in all other subpopulations following the current recommendations. Elevated Ctrough values were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctrough below 5 mg/l to >80%.\\n\\n\\nCONCLUSION\\nPharmacometric in silico studies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.\",\"PeriodicalId\":22111,\"journal\":{\"name\":\"Swiss medical weekly\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2024-04-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Swiss medical weekly\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.57187/s.3632\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MEDICINE, GENERAL & INTERNAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Swiss medical weekly","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.57187/s.3632","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, GENERAL & INTERNAL","Score":null,"Total":0}
Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology - application to amikacin.
BACKGROUND AND AIMS
Pharmacometric in silico approaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study.
METHODS
Amikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30-35 weeks and a post-natal age of 0-14 days ("subpopulation of clinical concern"), as potentially oto-/nephrotoxic trough concentrations (Ctrough >5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough (Ctrough <5 mg/l) dosages in most neonates.
RESULTS
In the subpopulation of clinical concern, Ctrough <5 mg/l was predicted in 59% versus 79-99% of cases in all other subpopulations following the current recommendations. Elevated Ctrough values were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctrough below 5 mg/l to >80%.
CONCLUSION
Pharmacometric in silico studies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.
期刊介绍:
The Swiss Medical Weekly accepts for consideration original and review articles from all fields of medicine. The quality of SMW publications is guaranteed by a consistent policy of rigorous single-blind peer review. All editorial decisions are made by research-active academics.