A physiologically based pharmacokinetic model for [⁶⁸Ga]Ga-(HA-)DOTATATE to predict whole-body distribution and tumor sink effects in GEP-NET patients.

Abstract

BACKGROUND

Little is known about parameters that have a relevant impact on (dis)similarities in biodistribution between various ⁶⁸Ga-labeled somatostatin analogues. Additionally, the effect of tumor burden on organ uptake remains unclear. Therefore, the aim of this study was to describe and compare organ and tumor distribution of [⁶⁸Ga]Ga-DOTATATE and [⁶⁸Ga]Ga-HA-DOTATATE using a physiologically based pharmacokinetic (PBPK) model and to identify factors that might cause biodistribution and tumor uptake differences between both peptides. In addition, the effect of tumor burden on peptide biodistribution in gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients was assessed.

CONCLUSION

The developed PBPK model adequately predicted tumor and organ uptake for this GEP-NET population. Relevant organ uptake differences between [⁶⁸Ga]Ga-DOTATATE and [⁶⁸Ga]Ga-HA-DOTATATE were caused by different affinity profiles, while tumor uptake was mainly affected by tumor blood flow and blood volume. Furthermore, tumor sink predictions showed that for the majority of patients a tumor sink effect is not expected to be clinically relevant.

METHODS

A PBPK model was developed for [⁶⁸Ga]Ga-(HA-)DOTATATE in GEP-NET patients. Three tumor compartments were added, representing primary tumor, liver metastases and other metastases. Furthermore, reactions describing receptor binding, internalization and recycling, renal clearance and intracellular degradation were added to the model. Scan data from GEP-NET patients were used for evaluation of model predictions. Simulations with increasing tumor volumes were performed to assess the tumor sink effect.

RESULTS

Data of 39 and 59 patients receiving [⁶⁸Ga]Ga-DOTATATE and [⁶⁸Ga]Ga-HA-DOTATATE, respectively, were included. Evaluations showed that the model adequately described image-based patient data and that different receptor affinities caused organ uptake dissimilarities between both peptides. Sensitivity analysis indicated that tumor blood flow and blood volume impacted tumor distribution most. Tumor sink predictions showed a decrease in spleen uptake with increasing tumor volume, which seemed clinically relevant for patients with total tumor volumes higher than ~ 550 mL.