Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer

P. Kellie Turner, Janet A. Houghton, I. Peták, David M. Tillman, Leslie Douglas, Lee Schwartzberg, Catherine A. Billups, John C. Panetta, Clinton F. Stewart

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 (AUC0 → ∞) and Cmax increased; however, significant interpatient variability was observed. IFN-γ AUC0 → ∞ 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.

Original languageEnglish
Pages (from-to)253-260
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume53
Issue number3
DOIs
Publication statusPublished - Mar 2004

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Pharmacodynamics
Pharmacokinetics
Interferon-gamma
Colorectal Neoplasms
Leucovorin
Blood Cells
Blood
Up-Regulation
Fluorouracil
HT29 Cells
Bioactivity

Keywords

  • Fas
  • IFN-γ
  • Pharmacodynamics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Turner, P. K., Houghton, J. A., Peták, I., Tillman, D. M., Douglas, L., Schwartzberg, L., ... Stewart, C. F. (2004). Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer. Cancer Chemotherapy and Pharmacology, 53(3), 253-260. https://doi.org/10.1007/s00280-003-0723-8

Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer. / Turner, P. Kellie; Houghton, Janet A.; Peták, I.; Tillman, David M.; Douglas, Leslie; Schwartzberg, Lee; Billups, Catherine A.; Panetta, John C.; Stewart, Clinton F.

In: Cancer Chemotherapy and Pharmacology, Vol. 53, No. 3, 03.2004, p. 253-260.

Research output: Contribution to journalArticle

Turner, PK, Houghton, JA, Peták, I, Tillman, DM, Douglas, L, Schwartzberg, L, Billups, CA, Panetta, JC & Stewart, CF 2004, 'Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer', Cancer Chemotherapy and Pharmacology, vol. 53, no. 3, pp. 253-260. https://doi.org/10.1007/s00280-003-0723-8
Turner, P. Kellie ; Houghton, Janet A. ; Peták, I. ; Tillman, David M. ; Douglas, Leslie ; Schwartzberg, Lee ; Billups, Catherine A. ; Panetta, John C. ; Stewart, Clinton F. / Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer. In: Cancer Chemotherapy and Pharmacology. 2004 ; Vol. 53, No. 3. pp. 253-260.
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