Dosimetry-Driven Alpha Emitter Selection for Radioligand Therapy: Is daughter translocation a significant safety concern?

PURPOSE

The first long-term safety data with a ²¹² Pb-labelled radiopharmaceutical reported significant renal adverse events after more than two years of follow-up. Understanding the pharmacokinetic drivers of dose delivery for alpha emitting radioligand therapy (RLT) will be critical to optimizing molecules. We aimed to model and compare the dosimetry and therapeutic index (TI) of a single pharmaceutical, rhPSMA-10.1, when labeled with either ²²⁵ Ac or ²¹² Pb, using human pharmacokinetic data.

METHODS

Dosimetry data from a Phase 1 trial of ¹⁷⁷ Lu-rhPSMA-10.1 in 13 mCRPC patients was used to generate time–activity curves for tumors and select organs-at-risk. These curves were used to model the dosimetry of ²²⁵ Ac-rhPSMA-10.1 and ²¹² Pb-rhPSMA-10.1 by substituting the physical half-life and decay properties of ¹⁷⁷ Lu with those of the alpha-emitters. Absorbed doses and TIs were calculated. The potential impact of daughter radionuclide translocation on organ doses and TIs was also modeled.

RESULTS

To deliver 5Gy _(RBE5) absorbed dose to tumors, a ∼29-fold higher administered activity of ²¹² Pb was required compared to ²²⁵ Ac (131 MBq versus 4.6 MBq, respectively). At this tumor dose, the activity of ²¹² Pb resulted in 2.5-fold and 2.2-fold higher absorbed doses to the kidneys and salivary glands, respectively, compared with ²²⁵ Ac. Consequently, ²²⁵ Ac demonstrated a substantially improved TI, with a ∼3-fold higher tumor:kidney dose ratio (9.85 versus 3.36) and a ∼2.2-fold higher tumor:salivary gland ratio (15.9 versus. 7.1). Even when modeling a worst-case scenario for daughter translocation, ²²⁵ Ac maintained a superior TI. Importantly, based on the pharmacokinetics of this drug, to achieve 120Gy _(RBE5) absorbed dose to tumors would require the delivery of 12.1Gy _(RBE5) and 35.7Gy _(RBE5) to the kidneys for ²²⁵ Ac and ²¹² Pb respectively. Modeling daughter translocation, these values become 39.1Gy _(RBE5) and 114.3Gy _(RBE5) respectively which may help to explain recently reported safety data from ²¹² Pb-labelled RLT.

CONCLUSIONS

The physical half-life of ²²⁵ Ac is better suited to the pharmacokinetic profile of rhPSMA-10.1 than the shorter half-life of ²¹² Pb. This results in substantially enhanced TI for ²²⁵ Ac-rhPSMA-10.1, permitting the delivery of markedly lower absorbed doses to organs-at-risk for a fixed tumor dose. Importantly, labelling with ²¹² Pb may lead to very high renal absorbed radiation doses driven predominantly by demetallation.

GRAPHICAL ABSTRACT