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Semimechanistic model to characterize nonlinear pharmacokinetics of nimotuzumab in patients with advanced breast cancer
Author(s) -
RodríguezVera Leyanis,
RamosSuzarte Mayra,
FernándezSánchez Eduardo,
Soriano Jorge Luis,
Guitart Concepción Peraire,
Hernández Gilberto Castañeda,
JacoboCabral Carlos O.,
de Castro Suárez Niurys,
Codina Helena Colom
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.496
Subject(s) - nimotuzumab , pharmacokinetics , nonmem , pharmacology , elimination rate constant , monoclonal antibody , pharmacodynamics , volume of distribution , chemistry , medicine , oncology , antibody , immunology
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.