Population Pharmacokinetics of ABT-806, an Investigational Anti-Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibody, in Advanced Solid Tumor Types Likely to Either Over-Express Wild-Type EGFR or Express Variant III Mutant EGFR

• Published in: Clinical pharmacokinetics Vol. 54; no. 10; pp. 1071 - 1081
• Main Authors: Sharma, Shringi, Mittapalli, Rajendar K., Holen, Kyle D., Xiong, Hao
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2015; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - blood; Antibodies, Monoclonal, Humanized - immunology; Antibodies, Monoclonal, Humanized - pharmacokinetics; Body Weight; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Internal Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - immunology; Objective Function Value; Epidermal Growth Factor Receptor; Population Pharmacokinetic Model; Mutant Epidermal Growth Factor Receptor; Human Epidermal Growth Factor Receptor
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-015-0258-2

Background and Objectives ABT-806 is a veneered ‘humanized’ recombinant IgG1κ antibody that is specific for a unique epitope of human epidermal growth factor receptor (EGFR) expressed only on tumor cells with the EGFRde2-7 (EGFRvIII) deletion mutant as well as tumors with wild-type amplified receptors. We aimed to develop a population pharmacokinetic model of ABT-806 in cancer patients, and to evaluate fixed versus body weight-based dosing regimens. Methods The pharmacokinetics of ABT-806 were evaluated in a phase I, open-label study in cancer patients following intravenous infusion of ABT-806 every other week. A total of 587 serum concentrations of ABT-806 from 61 patients were analyzed using non-linear mixed–effects modeling. The impact of body weight-based and fixed dosing of ABT-806 was evaluated using a simulation approach. Results A two-compartment model with linear elimination was used to describe the serum concentration–time data of ABT-806. The population estimates of the apparent clearance from the central (CL c ) and peripheral (CL p ) compartments were 0.011 and 0.025 L/h, respectively. The apparent volume of distribution estimates of the central ( V 1 ) and peripheral ( V 2 ) compartments were 3.5 and 3.3 L, respectively. The estimates of inter-subject variability (percentage coefficient of variation) in CL c , CL p , V 1 , and V 2 were 38, 37, 20, and 48 %, respectively. Albumin on CL c and body weight on V 1 were statistically significant covariates; however, they explained 18 and 30 % of the inter-individual variability of clearance and V 1 , respectively. Simulation results indicated that fixed and body weight-based dosing regimens yield similar steady-state concentrations and overall variability. Conclusions ABT-806 demonstrated a unique pharmacokinetic profile compared to the marketed monoclonal antibodies against EGFR. The analysis indicates it is feasible to switch to fixed doses in subsequent clinical trials of ABT-806.