In vivo pharmacokinetic and pharmacodynamic behavior of NOV-002, a redox-modulating glutathione disulfide mimetic

Abstract #4. Session Title: Biochemical Modulators

NOV-002 is a novel formulation of oxidized glutathione (GSSG) currently in a pivotal Phase 3 clinical trial in advanced non-small cell lung cancer. In clinical trials conducted to date, NOV-002 administered in combination with standard chemotherapeutic regimens has resulted in increased efficacy (survival, tumor response) and improved tolerance of standard chemotherapy (e.g. enhanced hematological recovery, immune stimulation). Recently, we showed that the proliferative effects of NOV-002 in the pre-myeloid HL-60 cell line is commensurate with stress-induced S-glutathionylation and activation of kinase pathways (AKT, JAK2 and STAT5) that are known to regulate hematopoiesis. The present investigation was undertaken to characterize the plasma pharmacokinetics of NOV-002 in C57 black mice and to determine if the drug caused S-glutathionylation of plasma proteins that might be used as surrogate biomarkers for drug efficacy. Using HPLC-MS, NOV-002 was measured in plasma at various times following a single intraperitoneal dose. Peak plasma concentrations were observed 10 min following administration of NOV-002 and were diminished by 60 min. Fluorescence based methods were used for quantification of protein thiol content and three S-glutathionylated plasma proteins were identified by mass spectrometry, serine proteinase inhibitor, contrapsin, and a-1-antitrypsin1-6 precursor. These preclinical pharmacokinetic and pharmacodynamic results provide evidence that, as in cell systems, NOV-002 administration in vivo results in generation of a transient oxidative signal that may trigger a variety of redox-regulated biochemical cascades. Such correlates could help to understand and predict clinical responses to treatment with NOV-002.