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 (K(e0)=0.0015+/-0.000035h(-1)) and the time-independent sensitivity (C(50%)(ss), 9.23+/-0.17microg/ml; C(max,eff)(ss), 12.5microg/ml) components of its tumor growth delay action. This relationship was consistent with a sigmoidal E(max) pharmacodynamic model postulating a hypothetical effect compartment that permits us to estimate an effective steady-state concentration range (7.5-12microg/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<0.05). The median survival time in treated mice under non-cumulative regimen (72+/-10 days), predicted an increase in this parameter as compared to the control one (55+/-6 days). Finally, using the allometric paradigm, the empiric power equation for dose scaling across mammalian species allowed the calculation of the dosage schedule for further clinical trial. The estimated maintenance dose in human (70kg) was 200mg/m(2) to be given weekly, and the corresponding loading dose was 600mg/m(2).
Duconge
Jorge
J
Department of Pharmacology and Toxicology, Institute of Pharmacy and Foods, University of Havana, 222 St. and 23rd. Avenue, La Coronela, La Lisa, Havana 36 CP 13600, Cuba. jduconge@yahoo.com.mx
Castillo
Rubén
R
Crombet
Tania
T
Alvarez
Daniel
D
Matheu
Janet
J
Vecino
Gloria
G
Alonso
Katia
K
Beausoleil
Irene
I
Valenzuela
Carmen
C
Becquer
Maria A
MA
Fernández-Sánchez
Eduardo
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000276:immunology*; D006801:Humans; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000911:Antibodies, Monoclonal; D066246:ErbB Receptors