年龄和肾功能对接受异基因造血干细胞移植预处理的儿科和成年患者中氟达拉滨的药代动力学和蛋白结合特征的影响。
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.
机构信息
Department of Biochemistry, The Children's Hospital at Westmead, Westmead, NSW, 2145, Australia.
The Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, NSW, 2145, Australia.
出版信息
Eur J Clin Pharmacol. 2024 Dec;80(12):1967-1987. doi: 10.1007/s00228-024-03751-0. Epub 2024 Sep 19.
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/m 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.
目的
评估 211 例接受异基因造血干细胞移植预处理的患者（年龄 0.1-63.4 岁）中游离氟达拉滨（氟达拉滨的循环代谢物）的群体药代动力学。
方法
在氟达拉滨剂量为 10-50mg/m 并于 0.42-1.5 小时内输注后，在时间间隔采集血样以测量总（n=2480）和游离（n=1403）F-Ara-A 浓度。基于游离血浆浓度建立了三房室群体药代动力学模型，用于估计 F-Ara-A 游离药代动力学参数和游离分数（fu）。评估了包括肾小球滤过率（GFR）和月经后年龄（PMA）在内的多种协变量，以评估其纳入模型的可能性。
结果
基础人群的中央室（CLu）和隔室间清除率（Q2u、Q3u）的游离清除率（CLu）和间室间清除率（Q2u、Q3u）的群体平均估计值（±相对标准误差，%RSE）分别为 3.42±3%、6.54±24%和 1.47±16%/L/h/70kg。游离分布容积的群体平均估计值（%RSE）分别为中央室（V1u）和外周室（V2u、V3u）的 9.65±8%、8.17±9%和 16.4±10%/70kg，fu 为 0.877±1%。协变量模型的建立涉及将 F-Ara-A CLu 分为非肾（1.81±9%/L/h/70kg）和肾成分（1.02±9%*GFR/L/h/70kg）。对肾 CLu 应用了一个 S 型成熟因子，人群对成熟 50%时的 Hill 指数和 PMA 的平均估计值分别为 2.97±4%和 69.1±8%周。
结论
患者年龄和 GFR 是游离 F-Ara-A CLu 的预测因子。这有可能影响剂量需求。一旦经过外部验证，该模型将有助于通过目标浓度干预进行个体化剂量调整。
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