The impact of age and renal function on the pharmacokinetics and protein binding characteristics of fludarabine in paediatric and adult patients undergoing allogeneic haematopoietic stem cell transplantation conditioning.

IF 2.4 3区医学 Q3 PHARMACOLOGY & PHARMACY

European Journal of Clinical Pharmacology Pub Date : 2024-09-19 DOI:10.1007/s00228-024-03751-0

Christa E Nath, Sebastian P A Rosser, Kiran K Nath, Jason Chung, Stephen Larsen, John Gibson, Melissa Gabriel, Peter J Shaw, Steven J Keogh

{"title":"The impact of age and renal function on the pharmacokinetics and protein binding characteristics of fludarabine in paediatric and adult patients undergoing allogeneic haematopoietic stem cell transplantation conditioning.","authors":"Christa E Nath, Sebastian P A Rosser, Kiran K Nath, Jason Chung, Stephen Larsen, John Gibson, Melissa Gabriel, Peter J Shaw, Steven J Keogh","doi":"10.1007/s00228-024-03751-0","DOIUrl":null,"url":null,"abstract":"Aim: To evaluate the population pharmacokinetics of unbound F-Ara-A (the circulating metabolite of fludarabine) in 211 patients (age range, 0.1-63.4 years) undergoing allogeneic haematopoietic stem cell transplantation conditioning.Methods: Total (n = 2480) and unbound (n = 1403) F-Ara-A concentrations were measured in blood samples collected at timed intervals after fludarabine doses ranging from 10 to 50 mg/m2 and infused over 0.42-1.5 h. A three-compartment population pharmacokinetic model was developed based on unbound plasma concentrations and used to estimate F-Ara-A unbound pharmacokinetic parameters and fraction unbound (fu). A number of covariates, including glomerular filtration rate (GFR) and post-menstrual age (PMA), were evaluated for inclusion in the model.Results: The base population mean estimates ± relative standard error (%RSE) for unbound clearance from the central compartment (CLu) and inter-compartmental clearances (Q2u, Q3u) were 3.42 ± 3%, 6.54 ± 24% and 1.47 ± 16% L/h/70 kg, respectively. The population mean estimates (%RSE) for the unbound volume of distribution into the central (V1u) and peripheral compartments (V2u, V3u) were 9.65 ± 8%, 8.17 ± 9% and 16.4 ± 10% L/70 kg, respectively, and that for fu was 0.877 ± 1%. Covariate model development involved differentiating F-Ara-A CLu into non-renal (1.81 ± 9% L/h/70 kg) and renal components (1.02 ± 9%*GFR L/h/70 kg). A sigmoidal maturation factor was applied to renal CLu, with population mean estimates for the Hill exponent and PMA at 50% mature of 2.97 ± 4% and 69.1 ± 8% weeks, respectively.Conclusion: Patient age and GFR are predictors of unbound F-Ara-A CLu. This has the potential to impact dose requirements. Dose individualisation by target concentration intervention will be facilitated by this model once it is externally validated.","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.4000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Clinical Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00228-024-03751-0","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Aim: To evaluate the population pharmacokinetics of unbound F-Ara-A (the circulating metabolite of fludarabine) in 211 patients (age range, 0.1-63.4 years) undergoing allogeneic haematopoietic stem cell transplantation conditioning.

Methods: Total (n = 2480) and unbound (n = 1403) F-Ara-A concentrations were measured in blood samples collected at timed intervals after fludarabine doses ranging from 10 to 50 mg/m² and infused over 0.42-1.5 h. A three-compartment population pharmacokinetic model was developed based on unbound plasma concentrations and used to estimate F-Ara-A unbound pharmacokinetic parameters and fraction unbound (fu). A number of covariates, including glomerular filtration rate (GFR) and post-menstrual age (PMA), were evaluated for inclusion in the model.

Results: The base population mean estimates ± relative standard error (%RSE) for unbound clearance from the central compartment (CLu) and inter-compartmental clearances (Q2u, Q3u) were 3.42 ± 3%, 6.54 ± 24% and 1.47 ± 16% L/h/70 kg, respectively. The population mean estimates (%RSE) for the unbound volume of distribution into the central (V1u) and peripheral compartments (V2u, V3u) were 9.65 ± 8%, 8.17 ± 9% and 16.4 ± 10% L/70 kg, respectively, and that for fu was 0.877 ± 1%. Covariate model development involved differentiating F-Ara-A CLu into non-renal (1.81 ± 9% L/h/70 kg) and renal components (1.02 ± 9%*GFR L/h/70 kg). A sigmoidal maturation factor was applied to renal CLu, with population mean estimates for the Hill exponent and PMA at 50% mature of 2.97 ± 4% and 69.1 ± 8% weeks, respectively.

Conclusion: Patient age and GFR are predictors of unbound F-Ara-A CLu. This has the potential to impact dose requirements. Dose individualisation by target concentration intervention will be facilitated by this model once it is externally validated.

查看原文本刊更多论文

接受同种异体造血干细胞移植调理的儿童和成人患者的年龄和肾功能对氟达拉宾的药代动力学和蛋白结合特性的影响。

目的：评估211名接受异基因造血干细胞移植调理的患者（年龄在0.1-63.4岁之间）体内未结合的F-Ara-A（氟达拉滨的循环代谢产物）的群体药代动力学：根据非结合血浆浓度建立了三室群体药代动力学模型，并用于估算F-Ara-A非结合药代动力学参数和非结合率（fu）。评估了一些协变量，包括肾小球滤过率（GFR）和月经后年龄（PMA），以便将其纳入模型：中心区非结合清除率（CLu）和室间清除率（Q2u、Q3u）的基本人群平均估计值（± 相对标准误差，%RSE）分别为 3.42 ± 3%、6.54 ± 24% 和 1.47 ± 16% L/h/70 kg。进入中心区（V1u）和外周区（V2u、V3u）的未结合分布容积的人群平均估计值（%RSE）分别为 9.65 ± 8%、8.17 ± 9% 和 16.4 ± 10% 升/70 千克，而 fu 的人群平均估计值为 0.877 ± 1%。变量模型的建立包括将 F-Ara-A CLu 区分为非肾脏（1.81 ± 9% 升/小时/70 千克）和肾脏（1.02 ± 9%*GFR 升/小时/70 千克）两部分。对肾脏 CLu 采用了曲线成熟因子，50% 成熟时的希尔指数和 PMA 的人群平均估计值分别为 2.97 ± 4% 和 69.1 ± 8% 周：结论：患者年龄和肾小球滤过率是非结合 F-Ara-A CLu 的预测因素。这可能会影响剂量要求。该模型一旦通过外部验证，将有助于通过目标浓度干预进行剂量个体化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

European Journal of Clinical Pharmacology 医学-药学

CiteScore

5.40

自引率

3.40%

发文量

170

审稿时长

3-8 weeks

期刊介绍： The European Journal of Clinical Pharmacology publishes original papers on all aspects of clinical pharmacology and drug therapy in humans. Manuscripts are welcomed on the following topics: therapeutic trials, pharmacokinetics/pharmacodynamics, pharmacogenetics, drug metabolism, adverse drug reactions, drug interactions, all aspects of drug development, development relating to teaching in clinical pharmacology, pharmacoepidemiology, and matters relating to the rational prescribing and safe use of drugs. Methodological contributions relevant to these topics are also welcomed. Data from animal experiments are accepted only in the context of original data in man reported in the same paper. EJCP will only consider manuscripts describing the frequency of allelic variants in different populations if this information is linked to functional data or new interesting variants. Highly relevant differences in frequency with a major impact in drug therapy for the respective population may be submitted as a letter to the editor. Straightforward phase I pharmacokinetic or pharmacodynamic studies as parts of new drug development will only be considered for publication if the paper involves -a compound that is interesting and new in some basic or fundamental way, or -methods that are original in some basic sense, or -a highly unexpected outcome, or -conclusions that are scientifically novel in some basic or fundamental sense.