In Silico Dosimetry Study of Tc99m-Tetrofosmin in Children Using a Novel PBPK Model in Humans Built from SPECT Imaging Data,Pharmaceutical Research

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In Silico Dosimetry Study of Tc99m-Tetrofosmin in Children Using a Novel PBPK Model in Humans Built from SPECT Imaging Data
Pharmaceutical Research ( IF 3.5 ) Pub Date : 2022-10-19 , DOI: 10.1007/s11095-022-03412-w
Christos Kaikousidis _{1,

2} , Aristides Dokoumetzidis _{1,

2}

Affiliation

Purpose

The aim of this work is to develop a Physiologically Based Pharmacokinetic model (PBPK) for the radiopharmaceutical Tc99m-Tetrofosmin in humans, from literature SPECT imaging data, to carry out in-silico dosimetry studies in children and extrapolate dosing.

Methods

A whole body PBPK model was developed from literature data from humans of Tc99m-Tetrofosmin tissue distribution. A data driven approach to estimate partition coeffects, permeability parameters and clearances was carried out, while some parameters were determined using a standard in silico PBPK method. Paediatric PK data for all tissues were simulated by changing the physiological parameters from the adult to paediatric values. Absorbed and effective doses for children of all ages were calculated using S-values from literature of Tc99m that have been computed from anthropomorphic phantoms.

Results

Using the results from each tissue, satisfactory goodness-of-fit was achieved, assessed by visual inspection and a coefficient of determination of R² = 0.965 while all estimated parameters had good standard errors. Paediatric simulations of Tetrofosmin distribution showed that paediatric profiles are not very different to the those of adults. The effective doses per unit of administered activity for 15 yo, 10 yo, 5 yo and 1 yo children were calculated to be 1.2, 1.7, 2.6 and 4.8 times higher, respectively than the adult value. Based on these calculations maximum administered activity scale more than proportionately to body weight.

Conclusions

A PBPK model of tetrofosmin in adults has been developed from SPECT imaging data and was extrapolated to conduct in-silico dosimetry studies in children of all ages.

中文翻译：

使用从 SPECT 成像数据构建的新型人体 PBPK 模型对儿童 Tc99m-替曲膦进行计算机剂量学研究

目的

这项工作的目的是根据文献 SPECT 成像数据，为放射性药物 Tc99m-Tetrofosmin 开发基于生理学的药代动力学模型 (PBPK)，以对儿童进行计算机剂量学研究并推断剂量。

方法

全身 PBPK 模型是根据 Tc99m-替曲膦组织分布的人类文献数据开发的。采用数据驱动的方法来估计分配系数、渗透率参数和清除率，而一些参数是使用标准的计算机 PBPK 方法确定的。通过将生理参数从成人值更改为儿科值来模拟所有组织的儿科 PK 数据。所有年龄段儿童的吸收剂量和有效剂量均使用 Tc99m 文献中的 S 值进行计算，该值是根据拟人模型计算得出的。

结果

使用每个组织的结果，获得了令人满意的拟合优度，通过目视检查和确定系数 R ² = 0.965 进行评估，同时所有估计参数都具有良好的标准误差。Tetrofosmin 分布的儿科模拟表明，儿科概况与成人的概况并无太大差异。经计算，15 岁、10 岁、5 岁和 1 岁儿童每单位给药活动的有效剂量分别比成人值高 1.2、1.7、2.6 和 4.8 倍。基于这些计算，最大管理活动规模与体重成正比。