Flavie Audy1, Maud Hennion1, Elisabeth Rouits1
1Pharmalex Belgium
Introduction: Targeted Radionuclide Therapy (TRT) has emerged as a promising cancer treatment modality, offering significant advantages over existing approaches. This therapy combines radioactive compounds emitting cytotoxic radiation with target-specific molecules, such as small molecules, peptides, or antibodies. The targeting moiety selectively bind to and accumulates in the intended target site, allowing for localized delivery of the therapeutic radiation. Consequently, this rapidly growing field of nuclear medicine has demonstrated remarkable efficacy with minimal toxicity, leading to a substantial increase in treated patients [1]. Problematic: The complex pharmacokinetics (PK) of TRT pose challenges in developing population pharmacokinetic (popPK) models, often required by Health Authorities for dosing justification during drug development. PopPK modeling is a powerful tool for model-informed drug development and identifying variability sources and covariates affecting drug response. Its applicability to TRT is obvious but not straightforward. Dosimetry studies are more complex than traditional clinical pharmacology, requiring simultaneous consideration of both the radioactive payload decay and the biological properties of the carrier molecule for comprehensive biodistribution characterization. Methods: In the context of clinical development of TRT, it is crucial to emphasize the design of dosimetry studies. Following the administration of a TRT agent, dedicated Positron Emission Tomography / Single-Photon Emission Computed Tomography / Computed Tomography (PET/SPECT/CT) scans must be conducted, along with conventional blood sampling. This comprehensive approach is crucial for quantifying both the risk and benefits associated with radiopharmaceutical administration by determining the absorbed dose in each organs and target and/or metastases lesions. The selection of time points for dosimetry should be carefully selected based on both the physical half-life of the radiopharmaceutical and the biological half-life of the carrier, as these can differ significantly. It is essential to strike a dedicate balance between gathering comprehensive data and minimizing patient burden as poorly chosen time points may lead to misinterpretation of the radiopharmaceutical’s disposition and biodistribution patterns. Initial data scrutinization is achieved through non-compartmental analyses (NCA) and graphical assessments. A NCA of fraction of injected dose data reveals that the estimated half-life corresponds to the product’s effective half-life. This finding therefore indicates that the derived PK parameters simultaneously consider both biological disposition and physical decay of the radiopharmaceutical. This dual representation of biological and physical half-life in a single set of PK parameters presents a unique challenge in data interpretation. To address this complexity, it is necessary to understand and interpret data from decay- and non-decay-corrected analyses. The development of a popPK model can consequently be structured to include a central compartment representing the blood compartment, a compartment representing tumor lesions/metastases, individual compartments for each identified safety-critical organ, and a lumped compartment representing the rest of the body [2]. Results/Conclusions: This staggered approach begins by extracting the maximum information through graphical explorations and NCA. Subsequently, a multicompartment model is developed. While this model resembles a physiologically-based pharmacokinetic (PBPK) model, it adopts an empirical approach where PK parameters are not derived from predefined physiological processes and drug-specific parameters. This approach is expected to enhance future radioligand therapy research by adequately predicting radioactivity uptake in all compartments and simulating radioactivity-times curves. Based on these simulations, absorbed doses can be calculated using the Medical Internal Radiation Dose method. Furthermore, this approach would enable the use of a single optimized time point SPECT/CT scan to predict the absorbed dose to organs and lesions, thereby facilitating treatment management for the patient either from drug supply and clinical operation perspective. Ultimately, this optimized assessments and analyses approach is expected to support a robust and consolidated dosing strategy thus improving of the personalization of TRT therapy [3].
[1] Targeted Radionuclide Therapy: An Overview, Dash et al., Curr Radiopharm, 2013 [2] Population pharmacokinetic dosimetry model using imaging data to assess variability in pharmacokinetics of 177Lu- PSMA- 617 in prostate cancer patients, Siebinga et al., CPT Pharmacometrics Syst Pharmacol, 2023 [3] [68Ga]GaPSMA11 PET imaging as a predictor for absorbed doses in organs at risk and small lesions in [ 177Lu]LuPSMA617 treatment, Peters et al., European Journal of Nuclear and Molecular Imaging, 2022
Reference: PAGE 33 (2025) Abstr 11326 [www.page-meeting.org/?abstract=11326]
Poster: Methodology - New Modelling Approaches