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Population Pharmacokinetics of Humanized Monoclonal Antibody HuCC49CH2 and Murine Antibody CC49 in Colorectal Cancer Patients

From the Division of Pharmaceutics, College of Pharmacy (Ms Fang, Mr Hinkle, Mr Cao, Mr Gibbs, Dr Dalton, Dr Chan, Dr Sun); Surgical Oncology, James Cancer Hospital and Solove Research Institute (Dr Bloomston, Dr Saif, Dr Martin); The Ohio State University, Columbus, Ohio; the Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand (Dr Holford); Pharmacokinetics and Drug Metabolism, Amgen Inc, Thousand Oaks, California (Dr Xiao); and the Laboratory of Tumor Immunology and Biology, National Institute of Health, Bethesda, Maryland (Dr Schlom).

To predict the optimal time for surgery after antibody administration, the population pharmacokinetics of ¹²⁵I-HuCC49CH2 and ¹²⁵I-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 HuCC49CH2 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.

Key Words: Population pharmacokinetics • Bayesian estimation • RIGS

Address for reprints: Address for correspondence: Duxin Sun, PhD, Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 232 Parks Hall, 500 West 12th Avenue, Columbus, OH 43210.

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