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Biodistribution and Multi-Compartment Pharmacokinetic Analysis of a Targeted Alpha Particle Therapy.

Targeted alpha particle therapy (TAT) is ideal for treating disease while minimizing damage to surrounding non-targeted tissues due to short path-length and high linear energy transfer (LET). We developed a TAT for metastatic uveal melanoma, targeting the melanocortin 1 receptor (MC1R), which is expressed in 94% of uveal melanomas. Two versions of the therapy are being investigated: 225Ac-DOTA-Ahx-MC1RL (225Ac-Ahx) and 225Ac-DOTA-di-D-Glu-MC1RL (225Ac-di-D-Glu). The biodistribution (BD) from each was studied and a multi-compartment pharmacokinetic (PK) model was developed to describe drug distribution rates. Two groups of 16 SCID mice bearing high MC1R expressing tumors were intravenously injected with 225Ac-Ahx or 225Ac-di-D-Glu. After injection, 4 groups (n=4) were euthanized at 24, 96, 144, and 288 hour time-points for each cohort. Tumors and 13 other organs were harvested at each time point. Isomeric gamma spectra were measured in tissue samples using a scintillation gamma detector and converted to alpha activity using factors for gamma ray abundance per alpha decay. Time activity curves were calculated for each organ. A 5-compartment PK model was built with the following compartments: blood, tumor, normal tissue, kidney, and liver. This model is characterized by a system of 5 ordinary differential equations using mass action kinetics which describe uptake, inter-compartmental transitions and clearance rates. The ordinary differential equations were simultaneously solved and fit to experimental data using a genetic algorithm for optimization. The BD data show that both compounds have minimal distribution to organs at risk other than kidney and liver. The PK parameter estimates had less than 5% error. From these data, the 225Ac-Ahx showed larger and faster uptake in the liver. Both compounds had comparable uptake and clearance rates for other compartments. The BD and PK behavior for two targeted radiopharmaceuticals were investigated. The PK model fit the experimental data and provided insight into the kinetics of the compounds systematically.