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Mechanism-based receptor-binding model to describe the pharmacokinetic and pharmacodynamic of an anti-α5β1 integrin monoclonal antibody (volociximab) in cancer patients.
- Source :
- Cancer Chemotherapy & Pharmacology; Jan2010, Vol. 65 Issue 2, p207-217, 11p, 1 Diagram, 3 Charts, 5 Graphs
- Publication Year :
- 2010
-
Abstract
- Volociximab is a chimeric IgG<subscript>4</subscript> that is being developed as a novel first-in-class anti-angiogenic, α<subscript>5</subscript>β<subscript>1</subscript> integrin inhibitor for the treatment of solid tumors. A mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to investigate the dynamic interaction between volociximab concentrations and free monocyte α<subscript>5</subscript>β<subscript>1</subscript> integrin levels in cancer patients. Twenty-one cancer patients from six dose cohorts (0.5, 1.0, 2.5, 5.0, 10, and 15 mg/kg) were included in the analysis. The fully integrated receptor-binding PK/PD model was developed and fit simultaneously to the PK/PD data. A Monte-Carlo parametric expectation-maximization method implement in S-ADAPT program was used to obtain estimates of population parameters and inter- and intra-subject variability. The PK/PD time profiles were well described by the model and the parameters were estimated with good precision. The model was used to simulate PK/PD time profiles for multiple dose regimens at various dose levels, and the results suggested that the monocyte α<subscript>5</subscript>β<subscript>1</subscript> integrin binding was saturated (≤5% free) at week 16 in the majority of patients treated with volociximab doses ≥10 mg/kg IV every 2 weeks. The developed model is useful for anticipating the drug exposures and extent of volociximab binding to peripheral monocyte α<subscript>5</subscript>β<subscript>1</subscript> integrin in untested regimens and for optimizing the design of future clinical trials. [ABSTRACT FROM AUTHOR]
- Subjects :
- PHARMACOKINETICS
PHARMACODYNAMICS
MONOCLONAL antibodies
CANCER patients
INTEGRINS
Subjects
Details
- Language :
- English
- ISSN :
- 03445704
- Volume :
- 65
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Cancer Chemotherapy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 45235094
- Full Text :
- https://doi.org/10.1007/s00280-009-1023-8