Radioimmunotherapy with anti-CD66 antibody: improving the biodistribution using a physiologically based pharmacokinetic model.
To improve radioimmunotherapy with anti-CD66 antibody, a physiologically based pharmacokinetic (PBPK) model was developed that was capable of describing the biodistribution and extrapolating between different doses of anti-CD66 antibody.


METHODS
The biodistribution of the (111)In-labeled anti-CD66 antibody of 8 patients with acute leukemia was measured. The data were fitted to 2 PBPK models. Model A incorporated effective values for antibody binding, and model B explicitly described mono- and bivalent binding. The best model was selected using the corrected Akaike information criterion. The predictive power of the model was validated comparing simulations and (90)Y-anti-CD66 serum measurements. The amount of antibody (range, 0.1-4 mg) leading to the most favorable therapeutic distribution was determined using simulations.


RESULTS
Model B was better supported by the data. The fits of the selected model were good (adjusted R(2) > 0.91), and the estimated parameters were in a physiologically reasonable range. The median deviation of the predicted and measured (90)Y-anti-CD66 serum concentration values and the residence times were 24% (range, 17%-31%) and 9% (range, 1%-64%), respectively. The validated model predicted considerably different biodistributions for dosimetry and therapeutic settings. The smallest (0.1 mg) simulated amount of antibody resulted in the most favorable therapeutic biodistribution.


CONCLUSIONS
The developed model is capable of adequately describing the anti-CD66 antibody biodistribution and accurately predicting the time-activity serum curve of (90)Y-anti-CD66 antibody and the therapeutic serum residence time. Simulations indicate that an improvement of radioimmunotherapy with anti-CD66 antibody is achievable by reducing the amount of administered antibody; for example, the residence time of the red marrow could be increased by a factor of 1.9 +/- 0.3 using 0.27 mg of anti-CD66 antibody.
Klinik für Nuklearmedizin, Universität Ulm, Ulm, Germany.
Peter
P
Kletting
Thomas
T
Kull
Donald
D
Bunjes
Bettina
B
Mahren
Markus
M
Luster
Sven N
SN
Reske
Gerhard
G
Glatting
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D005260:Female; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000503:physiopathology / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016499:Radioimmunotherapy; D015203:Reproducibility of Results; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000737:chemistry
D000906:Antibodies; D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D015021:Yttrium Radioisotopes