In many circumstances of data fitting one has to choose the optimal fitting function or model among several alternatives. Criteria or tests on which this decision is based are necessary and have to be well selected. In this preliminary analysis the application of the corrected Akaike information criterion is demonstrated considering the example of determining pharmacokinetic parameters for the blood serum time activity curves of 111In-labeled anti-CD66 antibody. Another model selection criterion, the F-test, is used for comparison. For the investigated data the corrected Akaike information criterion has proved to be an effective and efficient approach, applicable to nested and non-nested models.

In peptide receptor radionuclide therapy with 90 Y-labeled DOTATATE, the kidney absorbed dose limits the maximum amount of total activity that can be safely administered in many patients. A higher tumor-to-kidney 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 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 physiologic parameters were taken from the literature. Individual model parameters were fitted to a series (n 5 12) of planar γ-camera and serum measurements ( 111 In-DOTATATE) of patients with meningioma or neuroendocrine tumors (NETs). Using the PBPK model and the individually estimated parameters, we determined the tumor, liver, spleen, and red marrow biologically effective doses (BEDs) for a maximal kidney BED (20 Gy 2.5 ) 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 less than 1 Gy 15 , 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 the 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 mLÁg −1 Ámin −1 , and NETs, 0.02-1 mLÁg −1 Ámin −1 ) and receptor density (meningioma, 5-34 nmolÁL −1 , and NETs, 7-35 nmolÁL −1 ). Using the proposed method, we identified the optimal amount and pertaining activity 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 90 Y-DOATATE therapy, both the administered amount of peptide and the activity should be optimized in treatment planning using the proposed method. This approach could also be adapted for therapy with other peptides.

The software tool with its underlying methodology can be employed to objectively and reproducibly estimate the time integrated activity coefficient and its standard error for most time activity data in molecular radiotherapy.

The aim of this work was to simulate the effect of prostate-specific membrane antigen (PSMA)-positive total tumor volume (TTV) on the biologically effective doses (BEDs) to tumors and organs at risk in patients with metastatic castration-resistant prostate cancer who are undergoing Lu-PSMA radioligand therapy. A physiologically based pharmacokinetic model was fitted to the data of 13 patients treated with Lu-PSMA I&T (a PSMA inhibitor for imaging and therapy). The tumor, kidney, and salivary gland BEDs were simulated for TTVs of 0.1-10 L. The activity and peptide amounts leading to an optimal tumor-to-kidneys BED ratio were also investigated. When the TTV was increased from 0.3 to 3 L, the simulated BEDs to tumors, kidneys, parotid glands, and submandibular glands decreased from 22 ± 15 to 11.0 ± 6.0 Gy, 6.5 ± 2.3 to 3.7 ± 1.4 Gy, 11.0 ± 2.7 to 6.4 ± 1.9 Gy, and 10.9 ± 2.7 to 6.3 ± 1.9 Gy, respectively (where the subscripts denote that an α/β of 1.49, 2.5, or 4.5 Gy was used to calculate the BED). The BED to the red marrow increased from 0.17 ± 0.05 to 0.32 ± 0.11 Gy For patients with a TTV of more than 0.3 L, the optimal amount of peptide was 273 ± 136 nmol and the optimal activity was 10.4 ± 4.4 GBq. This simulation study suggests that in patients with large PSMA-positive tumor volumes, higher activities and peptide amounts can be safely administered to maximize tumor BEDs without exceeding the tolerable BED to the organs at risk.

Purpose: An important assumption in dosimetry prior to radionuclide therapy is the equivalence of pretherapeutic and therapeutic biodistribution. In this study the authors investigate if this assumption is justified in sst2‐receptor targeting peptide therapy, as unequal amounts of peptide and different peptides for pretherapeutic measurements and therapy are commonly used. Methods: Physiologically based pharmacokinetic models were developed. Gamma camera and serum measurements of ten patients with metastasizing neuroendocrine tumors were conducted using111In‐DTPAOC. The most suitable model was selected using the corrected Akaike information criterion. Based on that model and the estimated individual parameters, predicted and measured 90Y‐DOTATATE excretions during therapy were compared. The residence times for the pretherapeutic (measured) and therapeutic scenarios (simulated) were calculated. Results: Predicted and measured therapeutic excretion differed in three patients by 10%, 31%, and 7%. The measured pretherapeutic and therapeutic excretion differed by 53%, 56%, and 52%. The simulated therapeutic residence times of kidney and tumor were 3.1 ± 0.6 and 2.5 ± 1.2 fold higher than the measured pretherapeutic ones. Conclusions: To avoid the introduction of unnecessary inaccuracy in dosimetry, using the same substance along with the same amount for pretherapeutic measurements and therapy is recommended.