Combining whole-body clearance, blood activity concentrations, and SPECT images to explore the biodistribution of a novel 212PbPb-PSMA-targeting therapy compared to a 177LuLu-PSMA pharmacokinetic model

The recently published phase 0 trial of 212 Pb-labelled PSMA-targeting AB001 for metastatic castration-resistant prostate cancer (mCRPC) showed potential for further clinical development. Here we combined blood, whole-body (WB) probe measurements, and SPECT/CT images to investigate the biodistribution of AB001. Three mCRPC patients were imaged by SPECT/CT twice post-injection of 10 MBq AB001, and WB activity and whole blood, plasma, and red blood cell (RBC) activity concentrations of 212 Pb and 212 Bi (measured pre- and post-equilibrium) were sampled at four timepoints. A 177 LuLu-PSMA pharmacokinetic (PK) model was adapted to AB001 by changing physical half-lives and combining it with an International Commission on Radiological Protection (ICRP) model for unbound bismuth. The PSMA PK model was also altered by fitting to WB and plasma clearance. 212 Pb liver, kidney, parotid gland, and blood activities measured from SPECT were compared to 212 Pb in the respective model compartments or to samples. Activity concentration was 11 times higher in plasma than RBC. The 212 Bi blood activity concentration was consistently lower than 212 Pb. The adapted 177 LuLu-PSMA PK model indicated similar PK for AB001 in blood, but comparison with SPECT images suggested different biodistributions. Adjusting the excretion rate from the 177 LuLu-PSMA-617 PK model by fitting to AB001 WB clearance gave poorer fit between predicted and measured plasma activity than the unaltered model. Adjusting the PK model according to the plasma activities slightly improved the fit of the model to the WB clearance measurements compared to the unadjusted model, but the biodistribution differences compared to SPECT remained. High i n vivo stability of AB001 was indicated by combination of instant thin-layer chromatography measurements, comparison of plasma and RBC time-activity curves, and modelling of unbound 212 Pb. While comparison of biokinetics of AB001 to 177 LuLu-PSMA indicated differences in biodistribution, there are considerable uncertainties in the approach, including use of population-based PK models, their applicability to AB001, and SPECT quantification. • Biodistribution of AB001 investigated by PK model comparison. • In vivo stability of AB001 implied by RBC vs plasma activity, ITLC, and modelling. • Different biodistribution compared to 177 LuLu-PSMA-617 indicated by SPECT imaging.