Data di Pubblicazione:
2008
Citazione:
Nonclinical Safety, Pharmacokinetics, and Pharmacodynamics of Atacicept / M. Carbonatto, P. Yu, M. Bertolino, E. Vigna, S. Steidler, L. Fava, C. Daghero, B. Roattino, M. Onidi, M. Ardizzone, S. Peano, J. Visich, D. Janszen, S. Dillon, R. Ponce. - In: TOXICOLOGICAL SCIENCES. - ISSN 1096-6080. - 105:1(2008 Sep), pp. 200-210. [10.1093/toxsci/kfn105]
Abstract:
Atacicept, a soluble recombinant fusion protein of the human
immunoglobulin (Ig) G1 Fc and the extracellular domain of the
human transmembrane activator and calcium modulator and
cyclophylin ligand interactor receptor, acts as an antagonist of
both B lymphocyte stimulator and a proliferating–inducing
ligand. Here we determined the nonclinical safety, pharmacokinetics
and pharmacodynamics of atacicept in mice and cynomolgus
monkeys. Subcutaneous atacicept treatment (twice weekly in
cynomolgus monkeys, three times weekly in mice) was generally
safe and well tolerated safe and well tolerated with dosing up to 10
mg/kg every other day for up to 39 weeks or up to 80 mg/kg when
dosed for 4 weeks. At a dose of 1 mg/kg subcutaneous (sc)
bioavailability of atacicept in mice and monkeys was 76 and 92%,
with a mean serum t1/2 of 44 and 179 h, respectively. In accord
with its anticipated mechanism of action, repeated administration
of atacicept decreased serum IgG concentrations up to 50%, IgM
concentrations >99%, and circulating mature B-cell concentrations
up to 60%. These effects were dose-related but reversible, as
determined in a 25-week follow-up period. Microscopically, B cells
numbers were reduced in the follicular marginal zone of the spleen
and the mantle surrounding germinal centers of the lymph nodes.
These data confirm the preclinical safety and the pharmacological
activity of atacicept and support its clinical development.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Autoimmune; Chronic; Immunotoxicity; Pharmaceuticals; Toxicity
Elenco autori:
C. M., Y. P., B. M., V. E., S. Steidler, F. L., D. C., R. B., O. M., A. M., P. S., V. J., J. D., D. S., P. R.
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