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J Clin Pharmacol ; 55(8): 888-98, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25760761

ABSTRACT

This study aimed (1) to develop a semimechanistic pharmacokinetic (PK) model for nimotuzumab in patients with advanced breast cancer and (2) to identify demographic, biochemical, and clinical predictive factors of the PK variability. Data from a phase 1 study were analyzed using the nonlinear mixed-effects approach (NONMEM). A target-mediated disposition model that included 2 open PK compartments, the monoclonal antibody (mAb)-target binding, and target and mAb-target complex turnovers best described the linear and nonlinear PK. Covariates had no influence on the PK parameters. The final parameter estimates were 19.93 L (steady-state volume), 0.0045-0.0172 L/h (range of total clearance values), 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), and 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 of the treatment. This model can be very useful for knowing the dosing schedules required for efficacy and supports further investigation of the pharmacokinetic/pharmacodynamic relationships of nimotuzumab to improve its therapeutic use.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Breast Neoplasms/metabolism , Models, Biological , Adult , ErbB Receptors/antagonists & inhibitors , Female , Humans , Middle Aged
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