PMID- 28402142
OWN - NLM
STAT- MEDLINE
DCOM- 20170928
LR  - 20170928
IS  - 1520-5762 (Electronic)
IS  - 0363-9045 (Linking)
VI  - 43
IP  - 9
DP  - 2017 Sep
TI  - Development of separation technology for the removal of radium-223 from targeted 
      thorium conjugate formulations. Part II: purification of targeted thorium 
      conjugates on cation exchange columns.
PG  - 1440-1449
LID - 10.1080/03639045.2017.1318906 [doi]
AB  - Tumor targeting pharmaceuticals will play a crucial role in future pharma 
      pipelines. The targeted thorium conjugate (TTC) therapeutic platform could 
      provide real benefit to patients, whereby targeting moieties like monoclonal 
      antibodies are radiolabelled with the alpha-emitting radionuclide thorium-227 
      ((227)Th, t(1/2) = 18.7 days). A potential problem could be the accumulation of 
      the long-lived daughter nuclide radium-223 ((223)Ra, t(1/2) = 11.4 days) in the 
      drug product during manufacturing and distribution. Therefore, the level of 
      (223)Ra must be standardized before administration to the patient. The focus in 
      this study has been the removal of (223)Ra, as the other progenies will have a 
      very limited stay in the formulation. In this study, the purification of TTCs 
      labeled with decayed (227)Th has been explored. Columns packed with a strong 
      cation exchange resin have been used to sequester (223)Ra. The separation of TTC 
      from (223)Ra has been evaluated as influenced by both formulation and process 
      parameters with a design of experiments (DOE) study; including citrate or acetate 
      buffer, pH, buffer concentration, presence or absence of pABA + EDTA, resin 
      amount and sodium chloride concentration. The aim was to achieve a separation 
      with high sorption of (223)Ra and accompanying low TTC sorption. The results were 
      analyzed by multivariate analysis. Four regression models of TTC and (223)Ra 
      sorption from citrate and acetate buffered formulations were developed. The 
      predictive accuracy of sorption in the four statistical models was given by 
      standard deviations and confidence intervals. The TTC sorption in citrate and 
      acetate buffered formulations was affected by the identical variables and the 
      variation in TTC sorption was comparable for the two models. However, the DOE 
      variables had a significantly stronger impact on the (223)Ra sorption in citrate 
      buffered formulations than the (223)Ra sorption in acetate buffer. An optimal 
      separation with a TTC sorption below 25% and (223)Ra sorption above 90% can be 
      achieved in both citrate and acetate buffered formulations. Stability studies of 
      radiochemical purity (RCP) indicated that the measured (227)Th values may be 
      partly due to free (227)Th and not TTC, but the results indicate that TTC 
      stability may be controlled by optimizing formulation parameters. Hence, the 
      sorption data and the regression models presented must be reviewed and further 
      explored with regard to what is known about the stability of the TTC in the 
      different buffered formulations.
FAU - Frenvik, Janne Olsen
AU  - Frenvik JO
AD  - a Bayer AS , Lysaker, Oslo , Norway.
FAU - Dyrstad, Knut
AU  - Dyrstad K
AD  - b KD Metrix , Spireaveien , Oslo , Norway.
FAU - Kristensen, Solveig
AU  - Kristensen S
AD  - c School of Pharmacy, University of Oslo , Blindern, Oslo , Norway.
FAU - Ryan, Olav B
AU  - Ryan OB
AD  - a Bayer AS , Lysaker, Oslo , Norway.
LA  - eng
PT  - Journal Article
DEP - 20170427
PL  - England
TA  - Drug Dev Ind Pharm
JT  - Drug development and industrial pharmacy
JID - 7802620
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Buffers)
RN  - 0 (Cations)
RN  - 0 (Radiopharmaceuticals)
RN  - 60YU5MIG9W (Thorium)
RN  - W90AYD6R3Q (Radium)
SB  - IM
MH  - Antibodies, Monoclonal/*chemistry/metabolism
MH  - Buffers
MH  - Cations/*chemistry
MH  - Chemistry, Pharmaceutical
MH  - Radiopharmaceuticals
MH  - Radium/*chemistry
MH  - Thorium/chemistry
OTO - NOTNLM
OT  - 223Ra
OT  - 227Th
OT  - alpha particle
OT  - cancer
OT  - radioimmunotherapy
OT  - targeted alpha therapy
OT  - targeted thorium conjugates
EDAT- 2017/04/13 06:00
MHDA- 2017/09/29 06:00
CRDT- 2017/04/13 06:00
PHST- 2017/04/13 06:00 [pubmed]
PHST- 2017/09/29 06:00 [medline]
PHST- 2017/04/13 06:00 [entrez]
AID - 10.1080/03639045.2017.1318906 [doi]
PST - ppublish
SO  - Drug Dev Ind Pharm. 2017 Sep;43(9):1440-1449. doi: 10.1080/03639045.2017.1318906. 
      Epub 2017 Apr 27.