A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors

H Siebinga,J H Beijnen,M P M Stokkel,A D R Huitema,J J M A Hendrikx,B J De Wit-Van Der Veen,T P C Dorlo

doi:10.1186/s13550-021-00821-7

Abstract

BackgroundPhysiologically based pharmacokinetic (PBPK) models combine drug-specific information with prior knowledge on the physiology and biology at the organism level. Whole-body PBPK models contain an explicit representation of the organs and tissue and are a tool to predict pharmacokinetic behavior of drugs. The aim of this study was to develop a PBPK model to describe organ distribution of 68Ga-DOTATATE in a population of patients without detectable neuroendocrine tumors (NETs).MethodsClinical 68Ga-DOTATATE PET/CT data from 41 patients without any detectable somatostatin receptor (SSTR) overexpressing tumors were included. Scans were performed at 45 min (range 30–60 min) after intravenous bolus injection of 68Ga-DOTATATE. Organ (spleen, liver, thyroid) and blood activity levels were derived from PET scans, and corresponding DOTATATE concentrations were calculated. A whole-body PBPK model was developed, including an internalization reaction, receptor recycling, enzymatic reaction for intracellular degradation and renal clearance. SSTR2 expression was added for several organs. Input parameters were fixed or estimated using a built-in Monte Carlo algorithm for parameter identification.Results68Ga-DOTATATE was administered with a median peptide amount of 12.3 µg (range 8.05–16.9 µg) labeled with 92.7 MBq (range 43.4–129.9 MBq). SSTR2 amounts for spleen, liver and thyroid were estimated at 4.40, 7.80 and 0.0108 nmol, respectively. Variability in observed organ concentrations was best described by variability in SSTR2 expression and differences in administered peptide amounts.ConclusionsTo conclude, biodistribution of 68Ga-DOTATATE was described with a whole-body PBPK model, where tissue distribution was mainly determined by variability in SSTR2 organ expression and differences in administered peptide amounts.

Highlights

Neuroendocrine tumors (NETs) are a heterogeneous family of malignancies that arise from neuroendocrine cells and are often expressed in the gastroenteropancreatic tract and the bronchopulmonary tree [1, 2]
neuroendocrine tumors (NETs) show an overexpression of somatostatin receptors (SSTRs), which offers the possibility for imaging and treatment
Controversies remain on the value of 68Ga-DOTATATE accumulation to predict response to peptide receptor radionuclide therapy (PRRT) and its role in patient selection [12, 13]

Summary

Introduction

Neuroendocrine tumors (NETs) are a heterogeneous family of malignancies that arise from neuroendocrine cells and are often expressed in the gastroenteropancreatic tract and the bronchopulmonary tree [1, 2]. Discrepancies between 68Ga- and 177Lu-DOTATATE accumulation in clinical studies are often explained by their retrospective nature and small patient series, this may rely on actual differences between the ligands in pharmacokinetic (PK) behavior and receptor interactions. Detailed knowledge on these aspects for both 68Ga- and 177Lu-DOTATATE is currently lacking, making interpretation of these complex interactions and subsequent optimization of clinical algorithms difficult. The aim of this study was to develop a PBPK model to describe organ distribution of 68Ga-DOTATATE in a population of patients without detectable neuroendocrine tumors (NETs)

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Conclusion