L. Rodríguez Vera, M. Ramos, E. Fernández, J.L. Soriano, G. Castañeda and H. Colom
Department of Pharmacy, Institute of Pharmacy and Foods, University of Havana, Cuba
Nimotuzumab is a humanized monoclonal antibody targeted to the extracellular domain of human epidermal growth factor receptor (EGFR). The aims of this study were to develop a population pharmacokinetic (PPK) model for nimotuzumab as well as to identify demographic, biochemical and clinical predictive factors of the pharmacokinetic variability. A phase I clinical study of nimotuzumab in advanced breast cancer patients was carried out. Nimotuzumab was administered weekly by intravenous continuous infusions over 10 weeks. Three patients were enrolled at each of the following fixed dose groups: 50, 100, 200 and 400 mg. Blood samples were drawn for pharmacokinetic assessments on weeks 1st (0-168 h) and 10th (until 624 h). A simultaneous population pharmacokinetic analysis of 443 concentration-time data from 12 patients was performed by the nonlinear mixed-effect model approach with NONMEM 7.2. The first-order conditional estimation method with interaction was used throughout the modelling process. The model that best described the nimotuzumab pharmacokinetics was a Quasi Steady State (QSS) approximation of the full Target Mediated Drug Disposition (TMDD) model. Between patient variability modeled assuming a lognormal distribution was associated with CL, Vc and Kss. An additive residual error on log-transformed data was applied. The final model parameter estimates were CL: 0.0007 L/h, Vc: 1.43 L, CLD: 0.0032 L/h, Vp: 18.5 L, Kss: 6.96 µg/mL, kint: 0.148 h-1, ksyn: 1.43 μg/mL·h-1, kdeg: 5.50 h-1. For the first time a mechanistic population pharmacokinetic model of nimotuzumab that characterize the non-linear pharmacokinetic behavior has been developed. None of the covariates tested showed influence on the pharmacokinetic parameters. The level of EGFR expression must be considered a PK-modifying tumor attribute due to the combination of nimotuzumab with doxorubicin+cyclophosphamide therapy. Further population analysis with larger sample sizes will be a very useful tool in support of the clinical evaluation of nimotuzumab effectiveness as well as for dose calculations.