Optimized peptide amount and activity for Y-90-labeled DOTATATE therapy

In peptide receptor radionuclide therapy with ⁹⁰Y-labeled DOTATATE, the kidney absorbed dose limits the maximum amount of total activity, which can be safely administered in many patients. A higher tumor to kidneys absorbed dose ratio might be achieved by optimizing the amount of injected peptide and activity, as recent studies have shown different degrees of receptor saturation for normal tissue and tumor. The aim of this work was to develop and to implement a modeling method for treatment planning to determine the optimal combination of peptide amount and pertaining therapeutic activity for each patient. Methods: A whole body physiologically based pharmacokinetic (PBPK) model was developed. General physiological parameters were taken from the literature. Individual model parameters were fitted to series (N = 12) of planar gamma camera and serum measurements (¹¹¹In-DOTATATE) of patients with meningioma or neuroendocrine tumors (NETs). Using the PBPK model and the individually estimated parameters, the tumor, liver, spleen and red marrow biologically effective doses (BED) for a maximal kidney BED (20 Gy2.5) were determined for different peptide amounts and activities. The optimal combination of peptide amount and activity for maximal tumor BED, considering the additional constraint of a red marrow BED < 1 Gy15, was individually quantified. Results: The PBPK model describes the biokinetic data well considering the criteria of visual inspection, the coefficients of determination, the relative standard errors (< 50%) and correlation of the parameters (< 0.8). All fitted parameters were in a physiologically reasonable range but varied considerably between patients, especially tumor perfusion (meningioma 0.1-1 ml•g-1•min-1 and NETs 0.02-1 ml•g-1•min-1) and receptor density (meningioma 5-34 nmol•L-1 and NETs 7-35 nmol•L-1). Using the proposed method, the optimal amount and pertaining activity was identified to be 76±46 nmol (118±71 µg) and 4.2±1.8 GBq for meningioma and 87±50 nmol (135±78 µg) and 5.1±2.8 GBq for NET patients. Conclusion: The presented work suggests that to achieve higher efficacy and safety for ⁹⁰Y-DOATATE therapy, both, the administered amount of peptide and activity should be optimized in treatment planning using the herein proposed method. This approach could also be adapted for therapy with other peptides.

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