1. Safety, pharmacokinetic, and pharmacodynamic evaluations of PI-2301, a potent immunomodulator, in a first-in-human, single-ascending-dose study in healthy volunteers.
- Author
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Kovalchin J, Krieger J, Collins K, Genova M, Augustyniak M, Masci A, Avril T, Gandon G, Patat A, Fauchoux N, Toutin C, Lacoste E, Patel U, Mascioli E, and Zanelli E
- Subjects
- Adolescent, Adult, Aged, Antibodies blood, Biomarkers blood, Cell Proliferation drug effects, Cells, Cultured, Chemokine CXCL10 blood, Chemokine CXCL9 blood, Dose-Response Relationship, Drug, Double-Blind Method, France, Humans, Immunologic Factors administration & dosage, Immunologic Factors adverse effects, Immunologic Factors blood, Immunologic Factors immunology, Injections, Subcutaneous, Interferon-gamma metabolism, Interleukin-13 metabolism, Lymphocyte Activation drug effects, Male, Middle Aged, Oligopeptides administration & dosage, Oligopeptides adverse effects, Oligopeptides blood, Oligopeptides immunology, Polymers administration & dosage, Polymers adverse effects, Proteins administration & dosage, Proteins adverse effects, Proteins immunology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Young Adult, Immunologic Factors pharmacokinetics, Oligopeptides pharmacokinetics, Polymers pharmacokinetics, Proteins pharmacokinetics
- Abstract
PI-2301 is an amino acid copolymer acting as an immunomodulator for the treatment of autoimmune diseases. The present study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics of PI-2301 in a single ascending dose, first-in-human study involving healthy, male adult volunteers. A total of 56 subjects were given a subcutaneous injection of PI-2301 ranging from 0.035 to 60 mg. The only consistent side effect was transient injection site reactions. We describe, for the first time, a pharmacokinetic assay to monitor amino acid copolymer concentration in human serum. PI-2301 was detected in the serum of subjects in the 10-, 30-, and 60-mg cohorts. Maximum serum concentration was achieved between 10 and 30 minutes postdosing with some compound detected 4 hours after dosing. PI-2301's lasting immunological properties were evident by an ex vivo recall assay showing T-cell proliferation and IL-13 production in subjects dosed with 1, 3, or 10 mg of PI-2301, up to 6 months after dosing. A transient increase in chemokine CXCL9 and CXCL10 plasma levels was seen in subjects dosed with 30 or 60 mg of PI-2301. These results are highly consistent with our preclinical findings and suggest that PI-2301 could facilitate the expansion of a favorable immune posture in patients with autoimmune disorders.
- Published
- 2011
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