Integrated pharmacokinetic–pharmacodynamic modeling and allometric scaling for optimizing the dosage regimen of the monoclonal ior EGF/r3 antibody

The multiple-dose strategy with the monoclonal ior EGF/r3 antibody, in xenograft bearing nude mice, was supported upon the basis of its integrated pharmacokinetic–pharmacodynamic relationship, according to both the temporal (Ke0=0.0015±0.000035h−1) and the time-independent sensitivity (C50%ss, 9.23±...

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Bibliographic Details
Published in:European journal of pharmaceutical sciences 2004-02, Vol.21 (2-3), p.261-270
Main Authors: Duconge, Jorge, Castillo, Rubén, Crombet, Tania, Alvarez, Daniel, Matheu, Janet, Vecino, Gloria, Alonso, Katia, Beausoleil, Irene, Valenzuela, Carmen, Becquer, Maria A, Fernández-Sánchez, Eduardo
Format: Article
Language:English
Subjects:
Allometric scaling
Animals
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal - pharmacokinetics
Antibodies, Monoclonal - pharmacology
Antineoplastic agents
Biological and medical sciences
Carcinoma, Non-Small-Cell Lung - metabolism
Dosage regimen
Dose-Response Relationship, Drug
General aspects
Humans
Injections, Intravenous
Integrated pharmacokinetic–pharmacodynamic
Lung Neoplasms - metabolism
Male
Medical sciences
Mice
Mice, Nude
Monoclonal antibody ior EGF/r3
Pharmacology. Drug treatments
Receptor, Epidermal Growth Factor - immunology
Survival time
Time Factors
Tumor growth delay
Xenograft Model Antitumor Assays - methods
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Summary:The multiple-dose strategy with the monoclonal ior EGF/r3 antibody, in xenograft bearing nude mice, was supported upon the basis of its integrated pharmacokinetic–pharmacodynamic relationship, according to both the temporal (Ke0=0.0015±0.000035h−1) and the time-independent sensitivity (C50%ss, 9.23±0.17μg/ml; Cmax,effss, 12.5μg/ml) components of its tumor growth delay action. This relationship was consistent with a sigmoidal Emax pharmacodynamic model postulating a hypothetical effect compartment that permits us to estimate an effective steady-state concentration range (7.5–12μg/ml). Using this information we calculated both the cumulative and non-cumulative dosage regimens to compare their response patterns with respect to the control group. It follows that the differences in the estimated tumor growth inhibition ratio were statistically significant between the control group and either of the treated ones (P
ISSN:0928-0987
1879-0720
DOI:10.1016/j.ejps.2003.10.015