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Use of a Target‐Mediated Drug Disposition Model to Predict the Human Pharmacokinetics and Target Occupancy of GC 1118, an Anti‐epidermal Growth Factor Receptor Antibody
Author(s) -
Park WanSu,
Han Seunghoon,
Lee Jongtae,
Hong Taegon,
Won Jonghwa,
Lim Yangmi,
Lee Kyuhyun,
Byun Han Yeul,
Yim DongSeok
Publication year - 2017
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12675
Subject(s) - pharmacokinetics , cetuximab , chemistry , epidermal growth factor receptor , volume of distribution , pharmacology , receptor , monoclonal antibody , antibody , biochemistry , biology , immunology
GC 1118 is an anti‐epidermal growth factor receptor ( EGFR ) monoclonal antibody that is currently under clinical development. In this study, the pharmacokinetics ( PK ) of GC 1118 were modelled in monkeys to predict human PK and receptor occupancy ( RO ) profiles. The serum concentrations of GC 1118 and its comparator (cetuximab) were assessed in monkeys with a non‐compartmental analysis and a target‐mediated drug disposition ( TMDD ) model after intravenous infusion (3–25 mg/kg) of these drugs. The scaling exponent of the EGFR synthesis rate was determined using a sensitivity analysis. The human cetuximab exposures were simulated by applying different exponents (0.7–1.0) for the EGFR synthesis rate in the allometric monkey PK model. Simulated C max and area under the curve values therein were compared with those previously reported in the literature to find the best exponent for the EGFR synthesis rate in human beings. The TMDD model appropriately described the monkey PK profile, which showed a decrease in clearance ( CL ; 1.2–0.4 ml/hr/kg) as the dose increased. The exponents for CL (0.75) and volume of distribution (Vd; 1.0) were used for the allometric scaling to predict human PK . The allometric coefficient for the EGFR synthesis rate chosen by the sensitivity analysis was 0.85, and the RO profiles that could not be measured experimentally were estimated based on the predicted concentrations of the total target and the drug–target complex. Our monkey TMDD model successfully predicts human PK and RO profiles of GC 1118 and can be used to determine the appropriate dose for a first‐in‐human study investigating this drug.