Résumé
AbstractIntroductionLutetium-177 (177Lu)-Dotatate (Lutathera®) is a peptide receptor radionuclide therapy (PRRT) used to treat unresectable or metastatic somatostatin-receptor-positive (SSTR) gastroenteropancreatic neuroendocrine tumors (GEP-NET). PRRT may induce early and late hematological toxicity. The aim of our monocentric study is to determine bone marrow absorbed dose by simultaneously analysing plasma and imaging data with PKPOP modeling and to compare them with results obtained by standard practices using image-based dosimetry in our institution. Material methodsPatients with GEP-NET were treated with PRRT between May 2015 and December 2021. Nine blood samples (5 mL) were collected at each cycle: at the end of 177Lu-Dotatate infusion and 1, 2, 4, 8, 16, 24, 72, and 144 h post-dose. Radioactivity was measured using a WIZARD 2 2480-0010 Gamma Counter. These data were used to calculate area-under-the-curve of 177Lu-Dotatate plasma (AUCBL) and bone marrow (AUCRM) concentrations by PKPOP approach using Nonlinear mixed-effects modeling with NONMEM®. The medullary absorbed dose (ADref) was calculated by dosimetric approach using PlanetDose®. AUCBL and AUCRM were converted to absorbed dose using Medical Internal Radiation Dose (MIRD) formalism to resp. ADBL and ADRM. Generated plots were observed (OBS) versus population (PRED) and individual (IPRED) predicted concentrationsResults111 patients of which 71 were included with bone marrow data. For the 15 patients with imaging dosimetry, 14 AUC were available at cycle 1 and 6 AUC at cycle 4, corresponding to a total of 20 cycles. 2139 plasma concentrations are included in the PKPOP model. Goodness-of-fit plots show that the PRED and IPRED concentrations concurred with OBS data for plasma and bone marrow concentrations. The mean [range] at cycle 1 was : AUCBL = 4547 MBq/L.h [1987 – 7036] and AUCRM = 4362 MBq/L.h [1907 – 6389]. The mean [range] of ADref = 0.044 Gy [0.021 – 0.087] at cycle 1 and 0.048 Gy [0.031 – 0.067] at cycle 4. The mean [range] of ADBL = 0.030 Gy [0.013 – 0.044] and of ADRM = 0.029 Gy [0.012- 0.042]. The mean [range] percentage of difference between absorbed dose as determined by PkPOP vs dosimetry was -31.8 % [-75 ; 19].ConclusionThese results suggest that our validated population pharmacokinetic approach can be used to determine bone marrow absorbed dose. Moreover, this model can be based on plasma data only, and does not require imaging data. This new approach can allow for more robust and practical monitoring of bone marrow exposure.