[177Lu]Lu-DOTATATE Population Pharmacokinetics and Dosimetry Modeling for Adolescent and Adult Patients with Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors.
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There is an unmet need for treatment options for adolescents with malignant advanced gastroenteropancreatic neuroendocrine tumors or pheochromocytomas and paragangliomas. Whether radiopharmaceutical therapy dosing strategies for adults are suitable for adolescents is unknown. This study compared the plasma exposure and cumulative absorbed radiation dose of [177Lu]Lu-DOTATATE (177Lu-DOTATATE) between adults and adolescents treated with 7.4 GBq for 4 cycles every 8 wk to assess the probability of adolescent doses exceeding predefined safety thresholds for kidney and bone marrow dosimetry. Methods: Population pharmacokinetics (popPK) and exposure-dosimetry models for 177Lu-DOTATATE, developed for adults, and simulations based on the exposure-dosimetry model, were used to determine sample size for the NETTER-P trial, assuming that the same dosage is administered to adolescents as to adults. Subsequently, a popPK model on adolescents and an exposure-dosimetry model on pooled adult and adolescent data were developed, and the results were compared with those from adult models. Results: PopPK models for adults and adolescents showed no significant covariate effects. Applying an adult dosimetry model to an adolescent population predicted median kidney and bone marrow dosimetry values below predefined safety threshold levels of 29 Gy or less and 2 Gy or less, respectively. PopPK modeling confirmed comparable 177Lu-DOTATATE exposure, and kidney and bone marrow dosimetry values were predicted to be largely below threshold levels. The observed proportions and median predicted probabilities of exceeding thresholds after 4 cycles were approximately 20% for kidney or significantly below 20% for bone marrow, which was considered an acceptable safety limit. Age and weight did not show a clinically significant impact on 177Lu-DOTATATE exposure or kidney and bone marrow dosimetry values, confirming that flat dosing at adult dosage is appropriate for adolescents. Conclusion: 177Lu-DOTATATE with 7.4 GBq of activity, administered over 4 cycles 8 wk apart, is a well-tolerated therapeutic dosing regimen for adolescent patients with gastroenteropancreatic neuroendocrine tumors or pheochromocytomas and paragangliomas.