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Clin Pharmacokinet. 2015 Oct;54(10):1071-81. doi: 10.1007/s40262-015-0258-2.

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.

Author information

1
Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., One North Waukegan Road, AP13A, North Chicago, IL, 60064, USA.
2
Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., One North Waukegan Road, AP13A, North Chicago, IL, 60064, USA. rajendar.mittapalli@abbvie.com.
3
Oncology Development, AbbVie Inc., North Chicago, IL, USA.

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.

PMID:
25761639
DOI:
10.1007/s40262-015-0258-2
[Indexed for MEDLINE]

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