Mechanism-based receptor-binding model to describe the pharmacokinetic and pharmacodynamic of an anti-α₅β₁ integrin monoclonal antibody (volociximab) in cancer patients.

Ng, Chee C.; Bai, S.; Takimoto, C. H.; Tang, M. T.; Tolcher, A. W.

Volociximab is a chimeric IgG4 that is being developed as a novel first-in-class anti-angiogenic, α5β1 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 α5β1 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 α5β1 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 α5β1 integrin in untested regimens and for optimizing the design of future clinical trials.

PHARMACOKINETICS; PHARMACODYNAMICS; MONOCLONAL antibodies; CANCER patients; INTEGRINS

Cancer Chemotherapy & Pharmacology, 2010, Vol 65, Issue 2, p207

0344-5704

Academic Journal

10.1007/s00280-009-1023-8