A Phase I–II, Open-Label, Multicenter Trial to Determine the Dosimetry and Safety of ^99mTc-Sestamibi in Pediatric Subjects

Abstract

Myocardial perfusion imaging has long been used off label by practitioners attending for children with cardiac aliments. To provide clinicians with evidence-based dosage recommendation, a phase I-II, open-label, nonrandomized, multicenter trial was therefore designed using 99m Tc-sestamibi in pediatric subjects (registered under www.clinicaltrials. gov identifier no. NCT00162045). Methods: Safety and pharmacokinetic data were collected from 78 subjects using either a 1-d imaging protocol (3.7-7.4 MBq/kg, followed by 11.1 MBq/kg) or a 2-d protocol (7.4 MBq/kg for both rest and stress). Anterior and posterior planar images were collected at 15 min, 1.5 h, 4 h, and 8 h. Blood and urine samples were collected at predetermined times. Results: Subjects included 39 children (mean age ± SD, 8.5 ± 2.04 y) and 39 adolescents (mean age ± SD, 13.6 ± 1.39 y). Mean estimated organ-absorbed doses to the upper large intestine, small intestine, gallbladder wall, and lower large intestines were 0.082, 0.043, 0.042, and 0.035 mSv/MBq, respectively. All patients tolerated the radiotracer without serious adverse effects. Significant differences were observed in the liver, upper large intestine contents, and small intestine contents between rest and stress imaging. The effective dose equivalent and effective dose averages were lower in adolescents than younger children (0.011 and 0.019 mSv/MBq, respectively; P , 0.0001). Percentage injected doses (%IDs) corrected for radioactive decay in all dosimetry-evaluable subjects at 15 min and 4 h were 1.9% and 1.2% in the myocardium. Similarly in the lungs, the %ID for all dosimetryevaluable subjects was 4.9% at 15 min after injection. At rest, the %ID in the liver decreased from a maximum of about 26% at 15 min to less than 9% at 90 min. With stress, values decreased from 15% to 7%, respectively. Conclusion: The estimates of radiation dosimetry, pharmacokinetic parameters, and safety profile in this study population are similar to published studies based on body-mass extrapolations from studies in adults. As such, applying current 99m Tc-sestamibi dosing regimens for 1-and 2-d protocols based on those extrapolations will result in the expected radiation dose in children and adolescents.

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

“…This means that using the adult "residence times" in children for dosimetry is not a very bad approximation. This result is in line with dosimetry studies carried out directly in children which find satisfactory agreement with adult studies [2].…”

“…The results of the dosimetry study are reasonable and confirm findings in other products, i.e. Sestamibi [2] where the paediatric 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 in a position to replace real clinical studies, saving time and resources, while minimising risks for patients and volunteers.…”

“…Phase 1 studies such as full body scans are difficult to conduct on healthy volunteers, as this is considered unethical, while if this is conducted in patients in a phase 2 rationale it is feasible but still difficult [ 2 ]. Therefore, dosage recommendations for radiopharmaceuticals in children largely use kinetics of adults.…”