Pharmacokinetics and pharmacodynamics of the erythropoietin Mimetibody construct CNTO 528 in healthy subjects.
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 (SC(50)), efficacy (S(max)) 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 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.


CONCLUSIONS
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.
Pérez-Ruixo
Juan José
JJ
Clinical Pharmacology, Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica, Beerse, Belgium.
Krzyzanski
Wojciech
W
Bouman-Thio
Esther
E
Miller
Bruce
B
Jang
Haishan
H
Bai
Stephen A
SA
Zhou
Honghui
H
Yohrling
Jennifer
J
Cohen
Adam
A
Burggraaf
Jacobus
J
Franson
Kari
K
Davis
Hugh M
HM
D000328:Adult; D000740:Anemia / Q000188:drug therapy; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003198:Computer Simulation; D054796:Drug Dosage Calculations; D004906:Erythrocyte Count; D004921:Erythropoietin; D006207:Half-Life; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007143:Immunoglobulin Heavy Chains; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010456:Peptides, Cyclic; D017467:Receptors, Erythropoietin / Q000819:agonists; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics; D017701:Reticulocyte Count; D012156:Reticulocytes / Q000187:drug effects; D016037:Single-Blind Method; D055815:Young Adult
D000911:Antibodies, Monoclonal; C534685:CNTO 528 monoclonal antibody; C099963:EPO mimetic peptide 1; D006454:Hemoglobins; D007143:Immunoglobulin Heavy Chains; D010456:Peptides, Cyclic; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin