Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer

Abstract

Purpose

The study objectives were to define subcutaneous (s.c.) interferon gamma (IFN-γ) disposition in patients with gastrointestinal malignancies receiving 5-fluorouracil (5-FU) and leucovorin (LV) and to examine the relationship between IFN-γ exposures and Fas upregulation in vivo and in vitro.

Methods

Patients received IFN-γ (10, 25, 50, 75, and 100 μg/m²) with LV and 5-FU, and serial samples were collected after the first dose. IFN-γ concentrations were measured by ELISA. A linear one-compartment model with a lag was fitted to the IFN-γ plasma concentration-time data. To examine the relationship between IFN-γ systemic exposure and biological activity in vivo, cell surface Fas upregulation was assessed in peripheral blood mononuclear cell (PBMC) subcompartments.

Results

The median (range) apparent IFN-γ clearance was 46 l/m² per hour (2.6–92 l/m² per hour). With increasing IFN-γ dosages, the area under the concentration-time curve (AUC_0→∞) and C_max increased; however, significant interpatient variability was observed. IFN-γ AUC_0→∞ and time above 33.3 pg/ml significantly correlated with Fas upregulation in several PBMC compartments, but dosage was significantly correlated with this pharmacodynamic marker only in CD4⁺ and CD56⁺ cells. In vitro studies in HT29 cells demonstrated that clinically relevant IFN-γ concentrations (1 to 10 U/ml for 6.5 h) with 5-FU/LV upregulated Fas expression 3.5-fold, similar to that in PBMC in vivo.

Conclusions

We characterized IFN-γ disposition and developed a limited sampling model for use in future pharmacokinetic studies. Our results showed that IFN-γ upregulates Fas in PBMC in vivo and in HT29 cells in vitro at tolerable, clinically relevant exposures and that monitoring IFN-γ pharmacokinetics/pharmacodynamics may be warranted in IFN-γ clinical use.