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±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