Mechanism-based receptor-binding model to describe the pharmacokinetic and pharmacodynamic of an anti-alpha(5)beta(1) integrin monoclonal antibody (volociximab) in cancer patients

Volociximab is a chimeric IgG(4) that is being developed as a novel first-in-class anti-angiogenic, alpha(5)beta(1) 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 alpha(5)beta(1) 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 alpha(5)beta(1) integrin binding was saturated (a parts per thousand currency sign5% free) at week 16 in the majority of patients treated with volociximab doses a parts per thousand yen10 mg/kg IV every 2 weeks. The developed model is useful for anticipating the drug exposures and extent of volociximab binding to peripheral monocyte alpha(5)beta(1) integrin in untested regimens and for optimizing the design of future clinical trials.