Feasibility study of applying ICRP biokinetic models for pharmacokinetic modelling of alpha-emitter thorium-227 used in targeted radionuclide therapy

Li, W.B.; Zhernosekov, K.; Höllriegl, V.; Meckel, M.; Ziegler, S.; Konijnenberg, M.W.; Shi, Kuangyu (2018). Feasibility study of applying ICRP biokinetic models for pharmacokinetic modelling of alpha-emitter thorium-227 used in targeted radionuclide therapy. European journal of nuclear medicine and molecular imaging, 45(S1), S125-S125. Springer-Verlag

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Aim: Targeted radionuclide therapy with Th-227 conjugated with
novel antibodies, e.g. CD33 and CD70 has been pre-clinically used
for treatment of myeloid leukaemia and renal cell carcinoma,
respectively. Furthermore, PSMA-targeted Th-227 conjugate PSMA-
TTC was recently developed for preclinical pharmacological
study of treatment of prostate cancer. The imaging of alpha-emitter
labelled radiopharmaceuticals in clinical practice is challenging.
Therefore theoretical modelling of bio-distributions of Th-227
and its immediate decay product Ra-223 and other progeny is
highly desired. Especially radiolabelled metabolites or unconjugated
daughters may lead to toxicity but also might be beneficial
in the case of unconjugated Ra-223 targeting metastatic bone
lesions. Materials and methods: The current ICRP systemic biokinetic
model structure and transfer parameters of thorium were
taken as the prior model and parameters for pharmacokinetic
modelling. Because the immediate decay product Ra-223 is another
high LET alpha-emitter which can potentially be toxic to
healthy tissues, the biokinetic model of radium was coupled to
that for Th-227. By doing so, the bio-distributions of Th-227 and
Ra-223 in human body can be simultaneously monitored. Furthermore,
other decay products were as well taken into account and
connected to Ra-223 as independent biokinetic models. Results:
Model predictions show that 67% of Th-227 leaves blood with a
clearance half-life of 6 h and deposits on the bone surface, 6%
of Th-227 deposits in the liver and 4.5% of Th-227 deposits in the
kidneys. The progeny Ra-223 deposits a similar activity in the alimentary
tract and in the liver as the parent Th-227. The retentions
of Ra-223 as progeny in kidneys and testes are about 8% of that
of parent Th-227. Conclusion: The modelled pharmacokinetic
bio-distributions of Th-227 and its decay products can be used as
start distributions for local kinetic analysis, such as bone surface,
volume, marrow and blood. The bio-distributions of decay products
can be further used for patient dosimetry assessments.

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