Juliane Rascher, Shen Cheng, Curtis Johnston, Sebastian Härtter, Wojtyniak Jan-Georg, Jan Marquard, Igor Tartakovsky, Lori M B Laffel
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The PK model included 223 observations from 74 patients receiving empagliflozin 10 mg and 25 mg and the PK/PD model used 394 observations from 103 patients receiving empagliflozin (n = 52) or placebo (n = 51).</p><p><strong>Results: </strong>Empagliflozin PK was well described by a 2-compartment model with sequential zero-order and first-order absorption, with tested covariate effects of sex, age, race and estimated glomerular filtration rate on apparent clearance, and fixed allometric exponents on apparent clearance, apparent central volume of distribution, apparent intercompartmental clearance and apparent peripheral volume of distribution. Simulations of area under the curve at steady state (AUC<sub>ss</sub>) demonstrated that adult and paediatric subjects exhibit similar AUC<sub>ss</sub>. The PK/PD data were adequately described by a turnover model with disease progression and AUC<sub>ss</sub> inhibiting the HbA<sub>1c</sub> synthesis through an inhibitory maximum effect relationship. Simulations showed that the placebo-adjusted HbA<sub>1c</sub> decrease at Week 26 in the paediatric population was larger than that in the adult population (-0.699 vs. -0.528%).</p><p><strong>Conclusion: </strong>A Bayesian estimation framework enabled the characterization of empagliflozin PK and PK/PD with a limited number of samples in paediatric patients aged 10-17 years. Overall, the results confirm 10 and 25 mg as the appropriate empagliflozin doses in paediatric patients aged 10-17 years with type 2 diabetes mellitus.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetics and pharmacodynamics of empagliflozin in paediatric patients aged 10-17 years with type 2 diabetes mellitus.\",\"authors\":\"Juliane Rascher, Shen Cheng, Curtis Johnston, Sebastian Härtter, Wojtyniak Jan-Georg, Jan Marquard, Igor Tartakovsky, Lori M B Laffel\",\"doi\":\"10.1002/bcp.70096\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aims: </strong>To characterize the pharmacokinetics (PK) and PK/pharmacodynamics (PD) regarding glycosylated haemoglobin (HbA<sub>1c</sub>) lowering using the paediatric data from DINAMO and to assess differences compared with adults.</p><p><strong>Methods: </strong>Population PK and PK/PD models previously developed for empagliflozin in adults and adolescents were re-estimated in a Bayesian framework. The PK model included 223 observations from 74 patients receiving empagliflozin 10 mg and 25 mg and the PK/PD model used 394 observations from 103 patients receiving empagliflozin (n = 52) or placebo (n = 51).</p><p><strong>Results: </strong>Empagliflozin PK was well described by a 2-compartment model with sequential zero-order and first-order absorption, with tested covariate effects of sex, age, race and estimated glomerular filtration rate on apparent clearance, and fixed allometric exponents on apparent clearance, apparent central volume of distribution, apparent intercompartmental clearance and apparent peripheral volume of distribution. Simulations of area under the curve at steady state (AUC<sub>ss</sub>) demonstrated that adult and paediatric subjects exhibit similar AUC<sub>ss</sub>. 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引用次数: 0
摘要
目的:利用DINAMO的儿童数据表征糖基化血红蛋白(HbA1c)降低的药代动力学(PK)和PK/药效学(PD),并评估与成人相比的差异。方法:在贝叶斯框架下重新估计先前为成人和青少年建立的恩格列净人群PK和PK/PD模型。PK模型包括74名接受恩帕列净10mg和25mg治疗的患者的223个观察结果,PK/PD模型包括103名接受恩帕列净(n = 52)或安慰剂(n = 51)的患者的394个观察结果。结果:恩格列净的PK可以用一个序贯零级和一阶吸收的2室模型很好地描述,并检验了性别、年龄、种族和估计肾小球滤过率对表观清除率的协变量影响,以及固定异速指数对表观清除率、表观中心分布容积、表观室间清除率和表观周围分布容积的协变量影响。对稳态曲线下面积(aucs)的模拟表明,成人和儿童受试者表现出相似的aucs。PK/PD数据可以通过疾病进展和auss通过抑制最大效应关系抑制HbA1c合成的转换模型充分描述。模拟显示,在治疗第26周,儿科人群经安慰剂调整后的HbA1c下降幅度大于成人人群(-0.699 vs -0.528%)。结论:贝叶斯估计框架能够在10-17岁儿童患者的有限样本中表征恩格列净的PK和PK/PD。总的来说,结果证实10和25mg是10-17岁2型糖尿病儿童患者适当的恩格列净剂量。
Pharmacokinetics and pharmacodynamics of empagliflozin in paediatric patients aged 10-17 years with type 2 diabetes mellitus.
Aims: To characterize the pharmacokinetics (PK) and PK/pharmacodynamics (PD) regarding glycosylated haemoglobin (HbA1c) lowering using the paediatric data from DINAMO and to assess differences compared with adults.
Methods: Population PK and PK/PD models previously developed for empagliflozin in adults and adolescents were re-estimated in a Bayesian framework. The PK model included 223 observations from 74 patients receiving empagliflozin 10 mg and 25 mg and the PK/PD model used 394 observations from 103 patients receiving empagliflozin (n = 52) or placebo (n = 51).
Results: Empagliflozin PK was well described by a 2-compartment model with sequential zero-order and first-order absorption, with tested covariate effects of sex, age, race and estimated glomerular filtration rate on apparent clearance, and fixed allometric exponents on apparent clearance, apparent central volume of distribution, apparent intercompartmental clearance and apparent peripheral volume of distribution. Simulations of area under the curve at steady state (AUCss) demonstrated that adult and paediatric subjects exhibit similar AUCss. The PK/PD data were adequately described by a turnover model with disease progression and AUCss inhibiting the HbA1c synthesis through an inhibitory maximum effect relationship. Simulations showed that the placebo-adjusted HbA1c decrease at Week 26 in the paediatric population was larger than that in the adult population (-0.699 vs. -0.528%).
Conclusion: A Bayesian estimation framework enabled the characterization of empagliflozin PK and PK/PD with a limited number of samples in paediatric patients aged 10-17 years. Overall, the results confirm 10 and 25 mg as the appropriate empagliflozin doses in paediatric patients aged 10-17 years with type 2 diabetes mellitus.
期刊介绍:
Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology features papers and reports on all aspects of drug action in humans: review articles, mini review articles, original papers, commentaries, editorials and letters. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. It also publishes research on new methods, new drugs and new approaches to treatment. The Journal is recognised as one of the leading publications in its field. It is online only, publishes open access research through its OnlineOpen programme and is published monthly.