J Clin Pharmacol
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CLINICAL STUDIES

A Single Administration of Recombinant Human Interleukin-12 Is Associated With Increased Expression Levels of Interferon-gamma and Signal Transducer and Activator of Transcription in Healthy Subjects

Caroline Trudeau, PhD, Monette M. Cotreau, PhD, Lucille Stonis, BA, RN, Kevin H. Dykstra, PhD, Judy L. Oestreicher, MS, Andrew Strahs, PhD, Andrew J. Dorner, PhD, Victor H. Van Cleave, PhD, William L. Trepicchio, PhD and Ullrich S. Schwertschlag, MD, PhD, FACP, FCP

From Experimental Medicine (Dr Trudeau, Dr Cotreau, Ms Stonis), Clinical Research and Development (Dr Dykstra), Discovery Medicine (Ms Oestreicher, Dr Dorner, Dr Schwertschlag), Clinical Biostatistics (Dr Strahs), Bioanalytical R&D (Drug, Safety, and Metabolism) (Dr Van Cleave), and Molecular Medicine (Dr Trepicchio), Wyeth Research, Cambridge, Massachusetts. Dr Dykstra is currently at Pharsight Corporation, Mountain View, California. Dr Trepicchio is currently at Millennium Pharmaceuticals, Cambridge, Massachusetts.

The objectives of this study were to assess the safety and tolerability of single doses of 1, 4, and 8 µg of recombinant human interleukin-12 (rhIL-12) administered subcutaneously to healthy subjects. The pharmacokinetics, pharmacodynamics, and pharmacogenomics of rhIL-12 were evaluated. Recombinant human IL-12 was well tolerated in these healthy male and female subjects. The most frequently reported adverse events were flu-like symptoms, which exhibited a dose-response relationship. Pharmacokinetic analysis suggested that serum IL-12 levels increased with dose. Analysis of serum levels indicated that interferon-{gamma} increased with the dose of rhIL-12, whereas IL-6 levels showed no changes with rhIL-12 treatment. The messenger ribonucleic acid expression of signal transducer and activator of transcription was significantly increased 24 hours after the administration of rhIL-12 for all dose groups versus placebo, and results indicated that the magnitude of increase may be dose dependent. This study suggests that interferon-{gamma} and signal transducer and activator of transcription are biomarkers of rhIL-12 activity.

Key Words: Interleukin-12 (IL-12) • interferon-{gamma}(IFN-{gamma}) • signal transducer and activator of transcription (STAT-1) • clinical trial • healthy volunteers

Address for reprints: Monette M. Cotreau, PhD, Wyeth Research, 35 Cambridge Park Drive, Cambridge, MA 02140.


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