This study aims i) to develop a semi-mechanistic pharmacokinetic (PK) model for nimotuzumab, in patients with advanced breast cancer ii) to identify demographic, biochemical and clinical predictive factors of the PK variability. Data from a phase I study were analyzed using the nonlinear mixed effects approach (NONMEM). A target-mediated disposition model that included two-open PK compartments, the mAb-target binding and target and mAb-target complex turnovers, described best the linear and non-linear PK. Covariates had no influence on the PK parameters. The final parameter estimates were 19.93 L (steady state volume), 0.0045 L/h-0.0172 L/h (total clearance values range), 6.96 μg/mL (steady state binding constant), 5.50 h-1 (target degradation rate constant), 1.43 (μg/mL) · h-1 (complex formation rate), 0.148 h-1 (complex internalization rate constant). The model described the effect of the mAb-target binding, and target and mAb-target complex turnovers on nimotuzumab PK. Simulations showed that doses above 200 mg maintained the 50% target occupancy during all the treatment. This model can be very useful to know the dosing schedules required for efficacy and supports further investigation on the pharmacokinetic/pharmacodynamic relationships of nimotuzumab in order to improve its therapeutic use.

 

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