title: Semimechanistic model to characterize nonlinear pharmacokinetics of nimotuzumab in patients with advanced breast cancer.
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.
authors.affiliation: Laboratory of Pharmacokinetic, Department of Pharmacology & Clinical Pharmacy, Institute of Pharmacy & Foods, University of Havana, Havana, Cuba.
authors.forename: Leyanis
authors.initials: L
authors.lastname: Rodríguez-Vera
authors.affiliation: Center of Molecular Immunology, Havana, Cuba.
authors.forename: Mayra
authors.initials: M
authors.lastname: Ramos-Suzarte
authors.affiliation: Center for Biological Evaluation and Research, Institute of Pharmacy & Foods, University of Havana, Havana, Cuba.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernández-Sánchez
authors.affiliation: Hermanos Ameijeiras Hospital, Havana Center, Havana, Cuba.
authors.forename: Jorge Luis
authors.initials: JL
authors.lastname: Soriano
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, University of Barcelona, Barcelona, Spain.
authors.forename: Concepción Peraire
authors.initials: CP
authors.lastname: Guitart
authors.affiliation: Department of Pharmacology, CINVESTAV-IPN, Mexico City, Mexico.
authors.forename: Gilberto Castañeda
authors.initials: GC
authors.lastname: Hernández
authors.affiliation: Department of Pharmacology, CINVESTAV-IPN, Mexico City, Mexico.
authors.forename: Carlos O
authors.initials: CO
authors.lastname: Jacobo-Cabral
authors.affiliation: Laboratory of Pharmacokinetic, Department of Pharmacology & Clinical Pharmacy, Institute of Pharmacy & Foods, University of Havana, Havana, Cuba.
authors.forename: Niurys
authors.initials: N
authors.lastname: de Castro Suárez
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, University of Barcelona, Barcelona, Spain.
authors.forename: Helena Colom
authors.initials: HC
authors.lastname: Codina
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C501466:nimotuzumab; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; NONMEM; breast cancer; nimotuzumab; semimechanistic