CLINICAL PHARMACOLOGY
ORTHOCLONE OKT3 reverses graft rejection, probably by blocking the function of T cells which play a major role in acute allograft rejection. OTHOCLONE OKT3 reacts with and blocks the function of a 20,000 dalton molecule (CD3) in the membrane of human T cells that has been associated in vitro with the antigen recognition structure of T cells and is essential for signal transduction. In in vitro cytolytic assays, ORTHOCLONE OKT3 blocks both the generation and function of effector cells. Binding of ORTHOCLONE OKT3 to T lymphocytes results in early activation of T cells, which leads to cytokine release, followed by blocking T cell functions. After termination of ORTHOCLONE OKT3 therapy, T cell function usually returns to normal within one week.
In vivo, ORTHOCLONE OKT3 reacts with most peripheral blood T cells and T cells in body tissues, but has not been found to react with other hematopoietic elements or other tissues of the body.
A rapid and concomitant decrease in the number of circulating CD3 positive cells, including those that are CD2, CD4, or CD8 positive has been observed in patients studied within minutes after the administration of ORTHOCLONE OKT3. This decrease in the number of CD3 positive T cells results from the specific interaction between ORTHOCLONE OKT3 and the CD3 antigen on the surface of all T lymphocytes. T cell activation results in the release of numerous cytokines/lymphokines, which are felt to be responsible for many of the acute clinical manifestations seen following ORTHOCLONE OKT3 administration. (See: WARNINGS: Cytokine Release Syndrome, Central Nervous System Events.)
While CD3 positive cells are not detectable between days two and seven, increasing numbers of circulating CD2, CD4, and CD8 positive cells have been observed. The presence of these CD2, CD4, and CD8 positive cells has not been shown to affect reversal of rejection. After termination of ORTHOCLONE OKT3 therapy, CD3 positive cells reappear rapidly and reach pre-treatment levels within a week. In some patients however, increasing numbers of CD3 positive cells have been observed prior to termination of ORTHOCLONE OKT3 therapy. This reappearance of CD3 positive cells has been attributed to the development of neutralizing antibodies to ORTHOCLONE OKT3, which in turn block its ability to bind to the CD3 antigen on T lymphocytes. (See: PRECAUTIONS: Sensitization.)
Pediatric patients are known to have higher CD3 lymphocyte counts than adults. Pediatric patients receiving ORTHOCLONE OKT®3 therapy often require progressively higher doses of ORTHOCLONE OKT3 to achieve depletion of CD3 positive cells (<25 cells/mm3) and ensure therapeutic ORTHOCLONE OKT3 serum concentrations (>800 ng/mL). (See: DOSAGE AND ADMINISTRATION; PRECAUTIONS: Laboratory Tests.)
Serum levels of ORTHOCLONE OKT3 are measurable using an enzyme-linked immunosorbent assay (ELISA). During the initial clinical trials in renal allograft rejection, in patients treated with 5 mg per day for 14 days, mean serum trough levels of the drug rose over the first three days and then averaged 900 ng/mL on days 3 to 14. Serum concentrations measured daily during treatment with ORTHOCLONE OKT3 in renal, hepatic, and cardiac allograft recipients revealed that pediatric patients less than 10 years of age have higher levels than patients 10–50 years of age. Subsequent clinical experience has demonstrated that serum levels greater than or equal to 800 ng/mL of ORTHOCLONE OKT3 blocks the function of cytotoxic T cells in vitro and in vivo. Reduced T cell clearance or low plasma ORTHOCLONE OKT3 levels provide a basis for adjusting ORTHOCLONE OKT3 dosage or for discontinuing therapy. (See: WARNINGS: Anaphylactic Reactions; PRECAUTIONS: Laboratory Tests; ADVERSE EVENTS: Hypersensitivity Reactions; DOSAGE AND ADMINISTRATION.)
Following administration of ORTHOCLONE OKT3 in vivo, leukocytes have been observed in cerebrospinal and peritoneal fluids. The mechanism for this effect is not completely understood, but probably is related to cytokines altering membrane permeability, rather than an active inflammatory process. (See: WARNINGS: Cytokine Release Syndrome, Central Nervous System Events.)
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