Population-based model selection for an accurate estimation of time-integrated activity using non-linear mixed-effects modelling

Purpose: Personalized treatment planning in Molecular Radiotherapy (MRT) with accurately determining the absorbed dose is highly desirable. The absorbed dose is calculated based on the Time-Integrated Activity (TIA) and the dose conversion factor. A crucial unresolved issue in MRT dosimetry is which fit function to use for the TIA calculation. A data-driven population-based fitting function selection could help solve this problem. Therefore, this project aims to develop and evaluate a method for accurately determining TIAs in MRT, which performs a Population-Based Model Selection within the framework of the Non-Linear Mixed-Effects (NLME-PBMS) model. Methods: Biokinetic data of a radioligand for the Prostate-Specific Membrane Antigen (PSMA) for cancer treatment were used. Eleven fit functions were derived from various parameterisations of mono-, bi-, and tri-exponential functions. The functions' fixed and random effects parameters were fitted (in the NLME framework) to the biokinetic data of all patients. The goodness of fit was assumed acceptable based on the visual inspection of the fitted curves and the coefficients of variation of the fitted fixed effects. The Akaike weight, the probability that the model is the best among the whole set of considered models, was used to select the fit function most supported by the data from the set of functions with acceptable goodness of fit. NLME-PBMS Model Averaging (MA) was performed with all functions having acceptable goodness of fit. The Root-Mean-Square Error (RMSE) of the calculated TIAs from individual-based model selection (IBMS), a shared-parameter population-based model selection (SP-PBMS) reported in the literature, and the functions from NLME-PBMS method to the TIAs from MA were calculated and analysed. The NLME-PBMS (MA) model was used as the reference as this model considers all relevant functions with corresponding Akaike weights. Results: The function f3a=A1e-λ1+λphyst+A2e-λphyst was selected as the function most supported by the data with an Akaike weight of (54 ± 11) %. Visual inspection of the fitted graphs and the RMSE values show that the NLME model selection method has a relatively better or equivalent performance than the IBMS or SP-PBMS methods. The RMSEs of the IBMS, SP-PBMS, and NLME-PBMS (f3a) methods are 7.4%, 8.8%, and 2.4%, respectively. Conclusion: A procedure including fitting function selection in a population-based method was developed to determine the best fit function for calculating TIAs in MRT for a given radiopharmaceutical, organ and set of biokinetic data. The technique combines standard practice approaches in pharmacokinetics, i.e. an Akaike-weight-based model selection and the NLME model framework.