Abstract
P1422
Introduction: Physiologically based pharmacokinetic (PBPK) modeling fine-tuned for radiopharmaceuticals holds great promise to optimize radiopharmaceutical therapy (RPT) plans. Current practice in RPT involves the utilization of a single bolus injection or short-time infusion of the radiopharmaceutical in each treatment cycle. It is of interest to study the effect of the various injection profiles on delivered absorbed doses of tumors and organs at risk (OAR). In this study, we developed a PBPK model to evaluate whether larger absorbed doses can be delivered to tumors and OARs per unit of injected radioactivity and whether this framework can act as a differential enhancer, i.e. enabling improved dose delivery to the tumor with respect to OARs.
Methods: We developed a PBPK model for 177Lu-PSMA targetting RPTs. Our developed model involves a system of ordinary differential equations (ODEs) simulating the kinetics of radiopharmaceuticals in the body that enables us to track the number of hot and cold radiopharmaceuticals in different organs at any time (the full structure of the model is shown in figure 1). We have used realistic population-measured values for the parameters of the model. We further validated our model, which we implemented on SimBiology Matlab, using real data (5 SPECT images acquired post-injection 177Lu-PSMA I&T; data by Kletting et al.). For model validation and matching the predicted time activity curves with the measured data, we fit 10 parameters summarized in table 1.
Our simulated injected radiopharmaceutical consists of 11.7 GBq 177Lu-PSMA with the specific activity of 104 MBq/µg (i.e. 16.28 nmol hot ligand and 91 nmol cold ligand). Two injection profiles were tested: 1) a single bolus injection, and 2) 11.7GBq injection distributed over multiple bolus injections (see table 2). We calculated the normalized efficacy (NE) (Eq. 1) for each OAR (i.e. kidneys, salivary glands, liver, and spleen) to quantify any difference between these strategies. We also studied NE for different tumor sizes. We calculated the multi-bolus therapeutic efficacy (Eq. 2), which is the area under the curve of the normalized efficacy for each experiment with a different tumor size.
Results: We found that distributing the injection of radiopharmaceuticals over several bolus injections increases the delivered dose to tumors as well as organs at risk (OARs). This is most certainly due to the fact that separating the bolus injection into several administrations reduces the saturation in the receptors (thus controls the linearity of the system) and this in turn enhances the PSMA targeting efficacy of the radiopharmaceuticals (see figure 1). However, in the sense of tumor-to-OAR dose ratios, this is not advantageous because the multi-bolus strategy can increase OAR doses at a higher proportion than tumor doses (see figure 2). Our results suggest that the multi-bolus injection strategy does not act as a differential enhancer. However, we observed that the therapeutic efficacy increases with tumor size (see figure 3).
Conclusions: We compared the absorbed dose values for different organs in single-bolus and multi-bolus injection profiles. We found that several bolus injections can reduce the saturation level of receptors and increases the delivered absorbed dose to the tumor. However, our results suggest that the multi-bolus injection profile does not act as a differential enhancer factor because the increase in delivered absorbed dose to OAR can be larger than the increase in absorbed dose to the tumor when compared to the single bolus injection.
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