Biodistribution and Multicompartment Pharmacokinetic Analysis of a Targeted α Particle Therapy

Targeted α
particle therapy (TAT) is ideal for treating disease while minimizing
damage to surrounding nontargeted 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 multicompartment pharmacokinetic (PK) model was developed to
describe drug distribution rates. Two groups of 16 severe combined
immunodeficient (SCID) mice bearing high MC1R expressing tumors were
intravenously injected with 225Ac-Ahx or 225Ac-di-d-Glu. After injection, four groups (n = 4) were euthanized at 24, 96, 144, and 288 h time points for each
cohort. Tumors and 13 other organs were harvested at each time point.
Isomeric γ spectra were measured in tissue samples using a scintillation
γ detector and converted to α activity using factors for
γ ray abundance per α decay. Time activity curves were
calculated for each organ. A five-compartment PK model was built with
the following compartments: blood, tumor, normal tissue, kidney, and
liver. This model is characterized by a system of five ordinary differential
equations using mass action kinetics, which describe uptake, intercompartmental
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 the kidney and liver.
The PK parameter estimates had less than 5% error. From these data, 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.