Monoclonal antibodies as one of these new potential therapeutic agents benefit from their ability to bind to specific structural targets leading to good clinical efficacy and a general lower incidence of adverse events than small molecule therapeutics ( Stern and Herrmann, 2005). Recent discoveries in biomolecular processes in tumour growth led to the evolution of new targeted therapies in cancer treatment ( Ross et al, 2003). When correlated to efficacy, this model could serve as a tool to guide dose selection for this ‘targeted’ cancer therapy. In addition, relevant and plausible covariates were identified and incorporated into the model. A robust population pharmacokinetic model for matuzumab was developed, including a nonlinear pharmacokinetic process. All parameters were estimated with good precision (RSE<39%). A covariate analysis identified weight having an influence on V 1 (+0.44% per kg) and CLL (+0.87% per kg). In total, interindividual variability on V max, CLL, V 1 and V 2 and interoccasion variability on CLL was 22–62% CV. Structural parameters were in agreement with immunoglobulin characteristics. Data were best described using a two-compartment model with the parameters central ( V 1) and peripheral distribution volume ( V 2), intercompartmental ( Q) and linear (CLL) clearance and an additional nonlinear elimination pathway ( K m, V max).
#Nonmem proportional additive error model software
For analysis, 90 patients with 1256 serum concentration–time data were simultaneously fitted using the software NONMEM™.
infusions with 11 different dosing regimens ranging from 400 to 2000 mg, q1w–q3w.
Matuzumab was administered as multiple 1 h i.v. A population pharmacokinetic model based on data from three phase I studies was to be developed including a covariate analysis to describe the concentration–time profiles of matuzumab, a novel humanised monoclonal antibody.