Population pharmacokinetics of humanized monoclonal antibody HuCC49deltaCH2 and murine antibody CC49 in colorectal cancer patients.
To predict the optimal time for surgery after antibody administration, the population pharmacokinetics of (125)I-HuCC49deltaCH2 and (125)I-CC49 were characterized in 55 patients with colorectal cancers. A 2-compartment linear model was used to fit the pharmacokinetic data. Model stability and performance were assessed using a visual predictive check procedure. Different clinical trial designs were evaluated by simulation in combination with Bayesian estimation method to predict the optimal time for surgery. The results showed that HuCC49deltaCH2 had 65% faster clearance from blood circulation and 24% shorter mean residence time than CC49. Population pharmacokinetic analysis identified body weight as the only covariate to explain between-subject variability in clearance, intercompartmental flow rate, and volume of distribution. Model predictions indicated a wide interval for the optimal time of surgery, suggesting that it would be beneficial to individualize the time of surgery for each patient by measurement of antibody disposition. Clinical trial designs with at least 3 measurements of antibody disposition were found to be better than an empirical direct observation method for the optimal prediction of surgery time.
Fang
Lanyan
L
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 232 Parks Hall, 500 West 12th Avenue, Columbus, OH 43210, USA.
Holford
Nicholas H G
NH
Hinkle
George
G
Cao
Xianhua
X
Xiao
Jim J
JJ
Bloomston
Mark
M
Gibbs
Seth
S
Saif
Osama Habib Al
OH
Dalton
James T
JT
Chan
Kenneth K
KK
Schlom
Jeffery
J
Martin
Edward W
EW
Sun
Duxin
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm / Q000276:immunology; D014408:Biomarkers, Tumor / Q000276:immunology; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000601:surgery*; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D016719:Radioimmunodetection
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; C091202:B72.3 antibody; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D007457:Iodine Radioisotopes; C047052:tumor-associated antigen 72