(W-068) Dose determination of Lutathera in adolescents via popPK and dosimetry modeling and simulation

Meemansa Sood, na – Principal Pharmacometrician, Novartis Pharmaceuticals Corporation; Fariba Khanshan, na – Associate Director, Novartis Pharmaceuticals Corporation; Peter McComarck, na – Gobal Head EDA Pharmacometrics, Novartis Pharmaceuticals Corporation; Lars Blumenstein, na – Director, Novartis Institutes for BioMedical Research; Yu-Yun Ho, na – Executive Director Pharmacometrics, Novartis Pharmaceuticals Corporation

Lutathera® is an approved drug for the treatment of somatostatin receptor-positive advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults. There is an unmet need for treatment options in adolescent patients with advanced GEP-NETs and Pheochromocytomas and Paragangliomas (PPGL). To accelerate the access of Lutathera as a potential treatment for adolescent patients, Novartis proposed full efficacy extrapolation approach from adults to adolescents based on expected similar efficacy in both populations, under the condition that the total Lutathera dose remains the same. This extrapolation was made by comparing the blood exposure and the cumulative radioactive dose in main organs at risk, kidney, and bone marrow (BM), using already established popPK and exposure-dosimetry models in adults. The full efficacy extrapolation follows the hypothesis that adolescents can be treated with the same dose as adults without significant risk of exceeding external beam radiation therapy (EBRT) thresholds. The aims included dose determination and justification of full adult dose of Lutathera in the adolescent population (12 to < 18 y) with GEP-NET or PPGL to confirm comparable blood exposure, exposure-dosimetry relationship, and applicability of flat dosing.

PopPK model development was performed based on radioactivity-blood PK for Cycle 1, including components of the structural, random effect, and residual error models. Covariates, such as age, creatinine clearance (CrCl), weight (WT), and body surface area (BSA), were tested for popPK and exposure-dosimetry models. Empirical models based on dose (exposure) and CrCl as predictors were used to predict kidney and BM dosimetry for adults. Scenario simulations based on the dosimetry models were performed to predict the probability of the median dosimetry values exceeding the EBRT thresholds for kidney and BM. Subsequently, the adult exposure-dosimetry models were updated to include the adolescent data, and the exposure-dosimetry relationship was compared between the two populations.

A two-compartment model with linear elimination without any covariates adequately described the Lutathera PK in adult and adolescents. The predicted exposure metrics from this popPK model was further used to confirm the similarity of exposure between two populations. A comparable exposure-dosimetry relationship for kidney and BM dosimetry in adults and adolescents was observed, with similar probabilities of median kidney and BM dosimetry remaining below defined EBRT thresholds (≤29 Gy and ≤2 Gy respectively). Neither exposure nor kidney and BM dosimetry were clinically relevantly impacted by patients' age and WT. Both popPK and exposure-dosimetry modeling and simulations in kidney and BM confirm the appropriateness of using of full adult dose 7.4 GBq Q8W over 4 cycles of Lutathera in the adolescent population (12 to < 18 y).

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