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.
Eur J Clin Pharmacol. 2024 Dec;80(12):1967-1987. doi: 10.1007/s00228-024-03751-0. Epub 2024 Sep 19.
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.
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.
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.
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.
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。
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。
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。
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。
