Estimation of main and total effect of PBPK parameters in Meningioma patients

Abstract

This study aims to identify the most important parameters in the Physiologically-Based Pharmacokinetic (PBPK) model of Peptide Receptor Radionuclide Therapy (PRRT). By knowing the size of the contribution of physiological parameters to the PBPK model, it can reduce the variability of the absorbed dose (AD) in organs at risk, such as the kidney and tumor between individuals. The small variability has the potential to increase the accuracy of planning individual radionuclide therapy treatments. This study uses the extended Fourier Amplitude Sensitivity Test (eFAST) Global Sensitivity Analysis method, the best variance-based global method in analyzing the PBPK model. A whole-body PBPK model that has been developed for treatment planning in PRRT therapy for meningioma patients (n = 7). The parameters of interest analyzed were organ receptor densities Rdens, organ flows f, organ release rates, and peptide binding rate. AD as the desired output from the eFAST algorithm by calculating Si and STi from each AD Kidney and AD Tumor. All parameters of interest are converted into the lognormal distribution. The sampling strategy based on eFAST sampling, the interference factor is equal to 4. To see the convergence of the convergence value of Si and STi , a simulation was performed with a total evaluation of 129, 257, 513, 1025, 2049, 4097, and 8193. The results of the simulation, inter-individual variability of tumor AD (coefficient of variation CV up to CV = 73%) was higher than that organ at risk (e.g. kidneys CV around 22%). Based on GSA analysis, the most important parameter determined the AD of tumors, tumors receptor density (Si = 0.8, S Ti = 0.93), kidneys AD was kidneys receptor density (Si = 0.66, STi = 0.71). After validating Si by fixing every parameter considered important, the results can reduce the CV of the kidney AD from 22% to 1%, with a decrease in CV presentation of around 95%. CV AD tumor 1 was reduced by 68% from CV 44% to 14%, and CV in tumor AD 2 from 72% to 17% with a reduced CV presentation of about 77%. It was concluded that receptor measurement is important because it can improve the accuracy of radionuclide therapy treatment.