Important pharmacokinetic parameters for individualization of ¹⁷⁷Lu-PSMA therapy: A global sensitivity analysis for a physiologically-based pharmacokinetic model

Purpose: The knowledge of the contribution of anatomical and physiological parameters to interindividual pharmacokinetic differences could potentially be used to improve individualized treatment planning for radionuclide therapy. The aim of this study was therefore to identify the physiologically based pharmacokinetic (PBPK) model parameters that determine the interindividual variability of absorbed doses (ADs) to kidneys and tumor lesions in therapy with ¹⁷⁷Lu-labeled PSMA-targeting radioligands. Methods: A global sensitivity analysis (GSA) with the extended Fourier Amplitude Sensitivity Test (eFAST) algorithm was performed. The whole-body PBPK model for PSMA-targeting radioligand therapy from our previous studies was used in this study. The model parameters of interest (input of the GSA) were the organ receptor densities [R₀], the organ blood flows f, and the organ release rates λ. These parameters were systematically sampled NE times according to their distribution in the patient population. The corresponding pharmacokinetics were simulated and the ADs (model output) to kidneys and tumor lesions were collected. The main effect (Formula presented.) and total effect (Formula presented.) were calculated using the eFAST algorithm based on the variability of the model output: The main effect (Formula presented.) of input parameter (Formula presented.) represents the reduction in variance of the output if the “true” value of parameter (Formula presented.) would be known. The total effect (Formula presented.) of an input parameter (Formula presented.) represents the proportion of variance remaining if the “true” values of all other input parameters except for (Formula presented.) are known. The numbers of samples NE were increased up to 8193 to check the stability (i.e., convergence) of the calculated main effects (Formula presented.) and total effects (Formula presented.). Results: From the simulations, the relative interindividual variability of ADs in the kidneys (coefficient of variation CV = 31%) was lower than that of ADs in the tumors (CV up to 59%). Based on the GSA, the most important parameters that determine the ADs to the kidneys were kidneys flow ((Formula presented.) = 0.36, (Formula presented.) = 0.43) and kidneys receptor density ((Formula presented.) = 0.25, (Formula presented.) = 0.30). Tumor receptor density was identified as the most important parameter determining the ADs to tumors ((Formula presented.) and (Formula presented.) up to 0.72). Conclusions: The results suggest that an accurate measurement of receptor density and flow before therapy could be a promising approach for developing an individualized treatment with ¹⁷⁷Lu-labeled PSMA-targeting radioligands.