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Juan José Pérez-Ruixo,
Wojciech Krzyzanski,
Esther Bouman-Thio, Bruce Miller,
Haishan Jang,
Stephen A. Bai,
Honghui Zhou,
Jennifer Yohrling,
Adam Cohen,
Jacobus Burggraaf,
Kari Franson,
Hugh M. Davis
[show abstract]
[hide abstract]
ABSTRACT: Background and Objective Anaemia is a serious comorbidity that is common in patients with renal failure or cancer. CNTO 528 is the first Mimetibody™ developed to mimic the effects of erythropoietin (EPO), a hormone that stimulates the production of red blood cells (RBCs). The objective of this study was to develop a pharmacokinetic and pharmacodynamic model for CNTO 528 in healthy male subjects.Methods A pharmacokinetic/pharmacodynamic model for CNTO 528 was developed to describe the serum concentration versus time profile and the pharmacological responses of percentage of reticulocytes, total RBC counts and haemoglobin concentration after a single intravenous administration of CNTO 528 at 0.03, 0.09, 0.3 and 0.9 mg/kg in 24 healthy subjects. An open, linear, two-compartment model was used to characterize the pharmacokinetic parameters of CNTO 528. A catenary cell production and lifespan loss model was used to fit the pharmacodynamic data, yielding estimates of drug potency (SC50), efficacy (Smax) and other pharmacodynamic parameters. Bootstrap and posterior predictive checks (PPC) were used to evaluate the model.Results Administration of CNTO 528 stimulated the production of reticulocytes, RBCs and haemoglobin. CNTO 528 exhibits a half-life of 141 hours, or approximately 5.9 days. The SC50 was estimated to be 0.37 mg/L, indicating that low serum CNTO 528 concentration was sufficient to produce pharmacological effects. Compared with historical controls, CNTO 528 Smax appears to be 2-fold higher than recombinant human EPO. Bootstrap analysis and PPCs confirmed the accuracy and precision in the parameter estimates and the adequacy of the model to describe the CNTO 528 pharmacokinetics and pharmacodynamics.Conclusion The mechanistic population model was suitable to characterize the pharmacokinetics and pharmacodynamics of intravenously administered CNTO 528 in healthy subjects. This qualified model is deemed appropriate to conduct clinical trial simulations and to support the decision-making process for dose selection in studies of EPO-stimulating agents.
Clinical Pharmacokinetics 08/2009; 48(9):601-613. · 5.40 Impact Factor
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Juan José Pérez-Ruixo,
Wojciech Krzyzanski,
Esther Bouman-Thio, Bruce Miller,
Haishan Jang,
Stephen A Bai,
Honghui Zhou,
Jennifer Yohrling,
Adam Cohen,
Jacobus Burggraaf,
Kari Franson,
Hugh M Davis
[show abstract]
[hide abstract]
ABSTRACT: Anaemia is a serious comorbidity that is common in patients with renal failure or cancer. CNTO 528 is the first Mimetibody developed to mimic the effects of erythropoietin (EPO), a hormone that stimulates the production of red blood cells (RBCs). The objective of this study was to develop a pharmacokinetic and pharmacodynamic model for CNTO 528 in healthy male subjects.
A pharmacokinetic/pharmacodynamic model for CNTO 528 was developed to describe the serum concentration versus time profile and the pharmacological responses of percentage of reticulocytes, total RBC counts and haemoglobin concentration after a single intravenous administration of CNTO 528 at 0.03, 0.09, 0.3 and 0.9 mg/kg in 24 healthy subjects. An open, linear, two-compartment model was used to characterize the pharmacokinetic parameters of CNTO 528. A catenary cell production and lifespan loss model was used to fit the pharmacodynamic data, yielding estimates of drug potency (SC(50)), efficacy (S(max)) and other pharmacodynamic parameters. Bootstrap and posterior predictive checks (PPC) were used to evaluate the model.
Administration of CNTO 528 stimulated the production of reticulocytes, RBCs and haemoglobin. CNTO 528 exhibits a half-life of 141 hours, or approximately 5.9 days. The SC(50) was estimated to be 0.37 mg/L, indicating that low serum CNTO 528 concentration was sufficient to produce pharmacological effects. Compared with historical controls, CNTO 528 S(max) appears to be 2-fold higher than recombinant human EPO. Bootstrap analysis and PPCs confirmed the accuracy and precision in the parameter estimates and the adequacy of the model to describe the CNTO 528 pharmacokinetics and pharmacodynamics.
The mechanistic population model was suitable to characterize the pharmacokinetics and pharmacodynamics of intravenously administered CNTO 528 in healthy subjects. This qualified model is deemed appropriate to conduct clinical trial simulations and to support the decision-making process for dose selection in studies of EPO-stimulating agents.
Clinical Pharmacokinetics 02/2009; 48(9):601-13. · 5.40 Impact Factor
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Esther Bouman-Thio,
Kari Franson, Bruce Miller,
John Getsy,
Adam Cohen,
Stephen A Bai,
Jennifer Yohrling,
Bart Frederick,
Stanley Marciniak,
Qun Jiao,
Haishan Jang,
Hugh Davis,
Jacobus Burggraaf
[show abstract]
[hide abstract]
ABSTRACT: The erythropoietin mimetic antibody fusion protein CNTO 528 was developed as a novel antibody fusion protein by constructing an active hematopoietic peptide onto an IgG1-based scaffold. This resulted in a molecule with a long circulating half-life and a prolonged effect of stimulating reticulocyte production and hemoglobin (Hgb) synthesis. To assess the safety, pharmacokinetics, and pharmacodynamics of CNTO 528, the authors gave 44 adult healthy male subjects single or fractionated doses of intravenous CNTO 528 or placebo. CNTO 528 was generally well tolerated. The maximum observed concentration (Cmax) and the area under the concentration versus time curve (AUC) increased in an approximately dose-dependent manner between the 0.09-mg/kg and 0.9-mg/kg doses. The maximum effect on the reticulocyte response occurred approximately 8 to 9 days after administration. A median increase in Hgb (> or =1 g/dL above baseline) was achieved 9 to 10 days after administration, with a maximum effect between 19 and 26 days. Two subjects in the 0.9-mg/kg dose group had elevated Hgb concentrations requiring phlebotomy. In this first-in-human study, CNTO 528 was well tolerated and effective in elevating and maintaining Hgb by at least 1 g/dL following a single intravenous administration, which suggests that an erythropoietin mimetic molecule, such as CNTO 528, may be an effective therapy for patients with anemia.
The Journal of Clinical Pharmacology 10/2008; 48(10):1197-207. · 2.91 Impact Factor
