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.

Abstract

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 (CLc) and peripheral (CLp) 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 CLc, CLp, V 1, and V 2 were 38, 37, 20, and 48 %, respectively. Albumin on CLc 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.

• Authors: Shringi Sharma, Rajendar K Mittapalli, Kyle D Holen, Hao Xiong
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 54 Issue 10 Pg. 1071-81 (Oct 2015) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 25761639 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Antibodies, Monoclonal, Humanized
• epidermal growth factor receptor VIII
• EGFR protein, human
• ErbB Receptors
• depatuxizumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (administration & dosage, blood, immunology, pharmacokinetics)
• Body Weight
• Dose-Response Relationship, Drug
• ErbB Receptors (antagonists & inhibitors, genetics, immunology)
• Female
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasms (blood, drug therapy, genetics, metabolism)