A simulation-based method to determine optimal sampling schedules for dosimetry in radioligand therapy.

AIM: For dosimetry in radioligand therapy, the time-integrated activity coefficients (TIACs) for organs at risk and for tumour lesions have to be determined. The used sampling scheme affects the TIACs and therefore the calculated absorbed doses. The aim of this work was to develop a general and flexible method, which analyses numerous clinically applicable sampling schedules using true time-activity curves (TACs) of virtual patients. METHOD: Nine virtual patients with true TACs of the tumours were created using a physiologically-based pharmacokinetic (PBPK) model and individual biokinetic data of five patients with neuroendocrine tumours and four with meningioma. 111In-DOTATATE was used for pre-therapeutic dosimetry. In total, 15,120 sampling schemes, each consisting of 4 time points, were investigated. Gaussian noise of different levels was added to the corresponding true time-activity points. A bi-exponential function was used to fit the simulated time-activity data. For each investigated sampling schedule, 1000 replications were performed. Patient-specific and population-specific optimal sampling schedules were determined using the relative root-mean-square error (rRMSE). Furthermore, the fractions of TIACs a˜ deviating >5% (fΔa˜>5%) and >10% (fΔa˜>10%) from the true TIAC a˜true were used for additional evaluations e.g. to investigate the effect of varying single time points. RESULTS: Almost all patient-specific and all population-specific optimal sampling schedules have t4≥96h for all noise levels. Changing the latest time point from the population-specific optimal time to e.g. 48h leads to a median increase of fΔa˜>10% from 0.1% to 88% for the lowest investigated noise level. Using the determined population-specific optimal schedules, results in more accurate and precise results than established schedules from the literature. CONCLUSION: A method of determining the optimal sampling schedule for dosimetry, which considers clinical working hours and measurement uncertainties, has been developed and applied. The simulation study shows that optimised sampling schedules result in high accuracy and precision of the determined TIACs.