In Silico Dosimetry Study of Tc99m-Tetrofosmin in Children Using a Novel PBPK Model in Humans Built from SPECT Imaging Data
Christos Kaikousidis and Aristides Dokoumetzidis
Department of Pharmacy, University of Athens / Athena Research Center
Introduction: 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 posology.
Objectives:
- Develop a full-body PBPK model using literature data from healthy male volunteers [1] of Tc99m-Tetrofosmin tissue distribution after IV administration.
- Simulate PK data in children after extrapolating model parameters.
- Determine posology in children based on safety by carrying out in silico dosimetry studies in various ages.
Methods: A PBPK model was considered with explicit compartments for the following tissues: Arterial and venous blood, heart, lung, liver, gallbladder, kidneys, GI, thyroid, skeletal muscle and adipose. Furthermore, a vascular and extravascular compartment was considered for each of tissue, namely for heart, lung, liver and kidneys while the model selection between this type of model and the simpler model with a single compartment was carried out by goodness of fit criteria. 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. Pediatric PK data for all tissues were simulated by changing the physiological parameters from the adult to pediatric values. More specifically, the AUC values for the activity profiles, as a fraction of the administered dose (Ns), for all tissues were calculated and these were multiplied by Dose Fraction values, also called S values, according to the standard procedure recommended by MIRD[2]. S values were obtained from the RADAR website [3] specifically for Tc99m and for ages 1, 5, 10, 15 years old and adult. These parameters have been calculated from computational anthropomorphic phantoms of appropriate ages [4]. They calculate the radiation contribution to each organ coming from the organ itself as well as from all other organs, after the injection of a radioactive agent. The absorbed dose per activity unit administered (mGy/MBq) for all tissues was then calculated as a sum of all dose fractions weighted by Ns and finally the effective dose per administered activity was calculated (E), in mSv/MBq units, by summing up the absorbed doses (HT) of all organs with appropriate weights (WT) according to ICRP103 2007 [5].
Results: Using the results from each tissue, satisfactory goodness-of-fit was achieved, assessed by visual inspection of the fit, a predicted versus observed plot and a coefficient of determination of R2 = 0.965 while all estimated parameters had good standard errors. More specifically four types of parameters were estimated: 1) blood partition coefficients (Kp values) for the lung, heart, kidney, liver, thyroid and one for the rest of the organs, 2) the vascular to extravascular Permeability- surface area product (PS) for the heart and kidney, 3) the renal and liver clearances (CL) and finally 4) the flow rate of the gallbladder. All these parameters were accurately estimated with relative standard errors below 40 % -aside from the gallbladder flowrate which was slightly higher (56 %). Pediatric simulations of Tetrofosmin distribution showed that pediatric 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 it was found that the maximum administered activity scales more than proportionately to body weight.
Conclusions: Overall, we have demonstrated a methodology to conduct an in-silico dosimetry study in children from adult data by developing a PBPK model in adults which can be extrapolated to children of all ages, by changing the physiological parameters. Furthermore, this study is one of the first to develop a PBPK model from imaging data directly in humans. The results of the dosimetry study are reasonable and confirm findings in other products, i.e. Sestamibi [6] where the pediatric study was similar to that of adults. This approach is in line with the prospect of in silico clinical trials which we believe in the future will have a higher impact and may be able to replace real clinical studies, saving time and resources, while minimizing risks for patients and volunteers.
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