Optimization of peptide receptor radionuclide therapy (PRRT) using physiologically based pharmacokinetic (PBPK) Modelling

• Applicants: Professor Dr. Ambros Beer; Professor Dr. Gerhard Glatting; Dr. Peter Kletting (†)
• Subject Area: Medical Physics, Biomedical Technology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259460327

In peptide receptor radionuclide therapy (PRRT) neuroendocrine tumours (NET) are selectively irradiated using radiolabelled peptides. The sst2 subtype of the somatostatin receptor family, which is highly expressed on NET cells, is used as target structure. The selectivity is limited by sst2 expression in other tissues such as the kidneys. Due to additional unspecific uptake, the kidney represents the dose limiting organ. Therefore, to increase efficiency in PRRT, the (individual) patient biokinetics has to be optimized. Partially successful is the coadministration of amino acids, which reduce the unspecific uptake in the kidneys. However, renal toxicity is still a relevant issue in daily practice. Furthermore, studies show that renal and tumour uptakes vary considerably between patients. Thus, to maximize the tumour dose and minimize the risk of renal damage, individual estimation of the absorbed doses prior to PRRT is needed. The data required for dosimetry are obtained using imaging techniques and serum measurements.The aim of this proposal is the improvement of the individual dosimetry by: 1. A general improvement of the dosimetric calculations by achieving a more accurate prediction of the activity distribution using an optimized measurement schedule. 2. An individual improvement of the biodistribution by optimizing quantities like the amount of labelled peptide. For this purpose physiologically based pharmacokinetic (PBPK) models will be developed to systematically investigate the influence of different quantities like the tumour size on the biodistribution. In contrast to more empirical models (like the commonly used sums of exponentials), PBPK models are advantageous as the respective parameters represent measureable quantities. They allow the prediction of the biodistribution for different external inputs such as the use of different peptides in the same patient. In addition, the physiological structure increases the understanding of the model.For dosimetry before PRRT the measurement schedules are not optimal regarding the number and the sampling time. Using the developed model and developed mathematical methods, the most suitable sampling times will be identified and the number of measurements will be reduced if possible.As a result, this project will create the foundations for more favourable biodistribution of the radioactively labelled peptide, an improved data sampling and optimal analysis of the data. This will finally lead to a more effective treatment of patients with NETs using PRRT.

• DFG Programme: Research Grants