Dosimetry-Driven Alpha Emitter Selection for Radioligand Therapy: A Real World Application comparing 225Ac with 212Pb

PURPOSEThe first long-term safety data with a 212Pb-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 225Ac or 212Pb, using human pharmacokinetic data. METHODSDosimetry data from a Phase 1 trial of 177Lu-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 225Ac-rhPSMA-10.1 and 212Pb-rhPSMA-10.1 by substituting the physical half-life and decay properties of 177Lu 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. RESULTSTo deliver 5Gy(RBE5) absorbed dose to tumors, a [~]29-fold higher administered activity of 212Pb was required compared to 225Ac (131 MBq versus 4.6 MBq, respectively). At this tumor dose, the activity of 212Pb resulted in 2.5-fold and 2.2-fold higher absorbed doses to the kidneys and salivary glands, respectively, compared with 225Ac. Consequently, 225Ac 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, 225Ac 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 225Ac and 212Pb 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 212Pb-labelled RLT. CONCLUSIONSThe physical half-life of 225Ac is better suited to the pharmacokinetic profile of rhPSMA-10.1 than the shorter half-life of 212Pb. This results in substantially enhanced TI for 225Ac-rhPSMA-10.1, permitting the delivery of markedly lower absorbed doses to organs-at-risk for a fixed tumor dose. Importantly, labelling with 212Pb may lead to very high renal absorbed radiation doses driven predominantly by demetallation. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/25333110v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@3b6dbdorg.highwire.dtl.DTLVardef@1a1a1c6org.highwire.dtl.DTLVardef@83cf00org.highwire.dtl.DTLVardef@18b1699_HPS_FORMAT_FIGEXP M_FIG C_FIG